Cyclohexane derivatives and their use as therapeutic agents

ABSTRACT

The present invention relates compounds of formula (I), wherein ring A is a phenyl or pyridyl ring; X represents a linker selected from the group consisting of formulae: (a), (b), (c), (d), and (e); and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 13 , R 14 , R 15 , R 16 , R 17 , R 21a  and R 21b  are as defined herein. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/GB01/102,145, filed May 16, 2001, whichclaims priority under 35 U.S.C. §119 from GB Application No. 0012240.8,filed May 19, 2000.

This invention relates to a class of gem-disubstituted cyclohexanederivatives which are useful as tachykinin antagonists. Moreparticularly, the compounds of the invention are useful as neurokinin 1(NK-1) receptor antagonists.

The present invention provides compounds of the formula (I):

wherein

ring A is a phenyl or pyridyl ring;

X represents a linker selected from the group consisting of:

R¹ represents hydroxy, C₁₋₆alkyl, fluoroC₁₋₆alkyl, C₂₋₆alkenyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₄alkoxy, fluoroC₁₋₆alkoxyC₁₋₄alkyl,C₂₋₆alkenyloxy, C₃₋₇cycloalkoxy, C₃₋₇cycloalkylC₁₋₄alkoxy, phenoxy,cyano, halogen, NR^(a)R^(b), SR^(a), SOR^(a), SO₂R^(a), OSO₂R^(a),NR^(a)COR^(c), COR^(a), CO₂R^(a) or CONR^(a)R^(b) where R^(a) and R^(b)each independently represent hydrogen, C₁₋₄alkyl, C₃₋₅cycloalkyl,fluoroC₁₋₄alkyl or CH₂CO₂C₁₋₄alkyl, and R^(c) represents C₁₋₆alkyl,C₁₋₆alkoxy, fluoroC₁₋₆alkyl or phenyl;

R² represents hydrogen, halogen, C₁₋₆alkyl or C₁₋₆alkoxy;

or when R² is adjacent to R¹, they may be joined together such thatthere is formed a 5- or 6-membered saturated or unsaturated ringcontaining one or two atoms selected from nitrogen, oxygen and sulphur,which ring is optionally substituted by a group selected from C₁₋₄alkyl,CF₃, ═O or ═S;

R³ represents hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl, C₁₋₆alkoxy,fluoroC₁₋₆alkoxy, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, cyano,SR^(a), SOR^(a), SO₂R^(a), NR^(a)R^(b), NR^(a)COR¹⁴, COR^(a), CO₂R^(a),CONR^(a)R^(b) or C₁₋₄alkyl substituted by cyano, CO₂R^(a) orCONR^(a)R^(b) where R^(a) and R^(b) are as previously defined;

or R³ represents a 5- or 6-membered aromatic heterocyclic groupcontaining 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen andsulphur, which group is optionally substituted by one or two groupsselected from C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl,C₃₋₇cycloalkylC₁₋₄alkyl, trifluoromethyl, OCF₃, NO₂, CN, SR^(a),SOR^(a), SO₂R^(a), COR^(a), CO₂R^(a), phenyl, —(CH₂)_(r)NR^(a)R^(b),—(CH₂)_(r)NR^(a)COR^(b), —(CH₂)_(r)CONR^(a)R^(b), or CH₂C(O)R^(a), whereR^(a) and R^(b) are as previously defined and r is zero, 1 or 2;

R⁴ is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, hydroxy, NO₂, CN, SR^(a), SOR^(a), SO₂R^(a), CO₂R^(a),CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₄alkyl substituted byC₁₋₄alkoxy, wherein R^(a) and R^(b) are as previously defined;

R⁵ is hydrogen, halogen, C₁₋₆alkyl, fluoroC₁₋₆alkyl or C₁₋₆alkoxysubstituted by C₁₋₄alkoxy,

R⁶ represents hydrogen, hydroxy or a C₁₋₄alkyl group optionallysubstituted by a hydroxy group;

R⁷ represents hydrogen, hydroxy, —(CH₂)_(n)NR⁸R⁹, —(CH₂)_(n)CO₂R^(a),carbocyclyl, C-linked heterocyclyl or heteroaryl;

or R⁶ and R⁷ together represent ═O, ═CHCO₂R^(a) or —O(CH₂)_(m)O—;

R⁸ and R⁹ each independently represent hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,hydroxyC₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl,(CH₂)_(q)heterocyclyl, CHO, C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)C₃₋₇cycloalkyl,C(O)(CH₂)_(q)aryl, C(O)(CH₂)_(q)heterocyclyl, C(O)(CH₂)_(p)NR^(a)R^(b),(CH₂)_(q)CO₂C₁₋₆alkyl, CO₂(CH₂)_(q)C₃₋₇cycloalkyl, CO₂(CH₂)_(q)aryl,CO₂(CH₂)_(q)heterocyclyl, CO₂(CH₂)_(p)NR^(a)R^(b),(CH₂)_(p)NR^(a)COR^(b), (CH₂)_(p)NR^(a)CO₂R^(b), (CH₂)_(q)CONR^(a)arylor (CH₂)_(q)CONR^(a)heterocyclyl where R^(a) and R^(b) are as previouslydefined;

or R⁸ and R⁹, together with the nitrogen atom to which they areattached, represent a heteroaliphatic ring selected from the groupconsisting of:

R¹⁰ and R¹¹ each independently represent hydrogen, halogen, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyC₁₋₆alkyl, fluoroC₁₋₆alkyl,C₁₋₆alkoxy, (CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (C₂₋₆alkenyl)aryl,(C₂₋₆alkynyl)aryl, (CH₂)_(q)heterocyclyl, (CH₂)_(q)NR^(a)R^(b),O(CH₂)_(q)C₃₋₇cycloalkyl, O(CH₂)_(q)aryl, O(CH₂)_(q)heterocyclyl,O(CH₂)_(p)NR^(a)R^(b), OC(O)C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, C(O)(CH₂)_(q)NR^(a)R^(b), CO₂H, CO₂C₁₋₆alkyl,CO₂(CH₂)_(q)C₃₋₇cycloalkyl, CO₂(CH₂)_(q)aryl, CO₂(CH₂)_(q)heterocyclylor CO₂(CH₂)_(p)NR^(a)R^(b), where R^(a) and R^(b) are as previouslydefined;

or, when they are attached to the same carbon atom, R¹⁰ and R¹¹ maytogether represent ═O, ═CHCO₂R^(a), —O(CH₂)_(m)O—, —CH₂O(CH₂)_(s)—,—CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—,—C(CH₃)₂OCH₂CH₂—, —CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—,—C(O)OC(CH₃)₂CH₂—, —C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(s)—, —OC(CH₃)₂CH₂CH₂—,—OCH₂C(CH₃)₂CH₂—, —OCH₂CH₂C(CH₃)₂—, —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—,—OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—, —OCH₂CH₂C(O)CH₂—, or a group ofthe formula

or, where they are attached to adjacent carbon atoms, R¹⁰ and R¹¹ maytogether represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹⁰ and R¹¹ maytogether form a fused benzene ring;

or, R¹⁰ and R¹¹ together form a C₁₋₂alkylene bridge across thepyrrolidine, piperidine or hexamethyleneimine ring to which they areattached;

R¹² represents hydrogen, C₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl,(CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl, CHO, C(O)C₁₋₆alkyl,C(O)(CH₂)_(q)C₃₋₇cycloalkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, CO₂C₁₋₆alkyl, CO₂(CH₂)_(q)C₃₋₇cycloalkyl,CO₂(CH₂)_(q)aryl, CO₂(CH₂)_(q)heterocyclyl or CO₂(CH₂)_(p)NR^(a)R^(b),where R^(a) and R^(b) are as previously defined;

or, where they are attached to adjacent carbon atoms, R¹² and R¹⁸ maytogether form a fused imidazolyl or triazolyl ring;

R¹³ represents hydrogen, C₁₋₆alkyl or C(O)C₁₋₆alkyl;

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ each independently represent hydrogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkenyl, hydroxyC₁₋₆alkyl, C₁₋₄alkoxyC₁₋₄alkyl,(CH₂)_(p)NR^(a)R^(b), CHO, C(O)C₁₋₆alkyl or CO₂C₁₋₆alkyl;

or, R¹⁴ and R¹⁵ together represent —CH₂CH₂—;

or, R¹⁶ and R¹⁷ together represent —CH₂CH₂—;

R¹⁸ and R¹⁹ each independently represent hydrogen, halogen, hydroxy,C₁₋₆alkyl or oxo (═O);

R²⁰ represents hydrogen, halogen, hydroxy, C₁₋₄alkyl, hydroxyC₁₋₄alkylor fluoroC₁₋₄alkyl;

R^(21a) represents hydrogen, halogen or hydroxy and R^(21b) representshydrogen;

or R^(21a) and R^(21b) both represent fluorine or together represent oxo(═O);

n is zero, 1 or 2;

m is 1 or 2;

p is 1, 2, 3 or 4;

q is zero, 1, 2, 3 or 4; and

s is 1, 2 or 3;

and pharmaceutically acceptable salts and N-oxides thereof.

According to an alternative embodiment, the present invention alsoprovides compounds of the formula (I′):

wherein

X represents a linker selected from the group consisting of:

R⁶ represents hydrogen or a C₁₋₄alkyl group optionally substituted by ahydroxy group;

R⁷ represents hydrogen, hydroxy, —(CH₂)_(n)NR⁸R⁹, —(CH₂)_(n)CO₂R^(a),carbocyclyl or heteroaryl;

or R⁶ and R⁷ together represent ═O, ═CHCO₂R^(a) or —O(CH₂)_(m)O—;

R⁸ and R⁹ each independently represent hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,(CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl, CHO,C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)C₃₋₇cycloalkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, C(O)(CH₂)_(p)NR^(a)R^(b),(CH₂)_(q)CO₂C₁₋₆alkyl, CO₂(CH₂)_(q)C₃₋₇cycloalkyl, CO₂(CH₂)_(q)aryl,CO₂(CH₂)_(q)heterocyclyl, CO₂(CH₂)_(p)NR^(a)R^(b),(CH₂)_(p)NR^(a)COR^(b) or (CH₂)_(p)NR^(a)CO₂R^(b), where R^(a) and R^(b)are as previously defined;

or R⁸ and R⁹, together with the nitrogen atom to which they areattached, represent a heteroaliphatic ring selected from the groupconsisting of:

R¹⁰ and R¹¹ each independently represent hydrogen, halogen, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,(CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (C₂₋₆alkenyl)aryl,(C₂₋₆alkynyl)aryl, (CH₂)_(q)heterocyclyl, (CH₂)_(q)NR^(a)R^(b),O(CH₂)_(q)C₃₋₇cycloalkyl, O(CH₂)_(q)aryl, O(CH₂)_(q)heterocyclyl,O(CH₂)_(p)NR^(a)R^(b), OC(O)C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, C(O)(CH₂)_(q)NR^(a)R^(b), CO₂H, CO₂C₁₋₆alkyl,CO₂(CH₂)_(q)C₃₋₇cycloalkyl, CO₂(CH₂)_(q)aryl, CO₂(CH₂)_(q)heterocyclylor CO₂(CH₂)_(p)NR^(a)R^(b), where R^(a) and R^(b) are as previouslydefined;

or, when they are attached to the same carbon atom, R¹⁰ and R¹¹ togetherrepresent ═O, ═CHCO₂R^(a), O(CH₂)_(m)O—, —OCH₂CH₂CH₂—, —CH₂OCH₂CH₂— or—CH₂OCH₂C(O)—;

or, where they are attached to adjacent carbon atoms, R¹⁰ and R¹¹together form a fused benzene ring;

or, R¹⁰ and R¹¹ together form a C₁₋₂alkylene bridge across thepyrrolidine, piperidine or hexamethyleneimine ring to which they areattached;

R¹² represents hydrogen, C₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl,(CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl, CHO, C(O)C₁₋₆alkyl,C(O)(CH₂)_(q)C₃₋₇cycloalkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, CO₂C₁₋₆alkyl, CO₂(CH₂)_(q)C₃₋₇cycloalkyl,CO₂(CH₂)_(q)aryl, CO₂(CH₂)_(q)heterocyclyl or CO₂(CH₂)_(p)NR^(a)R^(b),where R^(a) and R^(b) are as previously defined;

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ each independently represent hydrogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkenyl, hydroxyC₁₋₆alkyl, (CH₂)_(p)NR^(a)R^(b), CHO,C(O)C₁₋₆alkyl or CO₂C₁₋₆alkyl;

and R¹, R², R³, R⁴, R⁵, R¹³, n, m, p and q are as defined in relation toformula (I);

and pharmaceutically acceptable salts thereof.

A preferred class of compound of formula (I) is that wherein R¹ ishydroxy, C₁₋₆alkyl, fluoroC₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy,fluoroC₁₋₆alkoxy, C₂₋₆alkenyloxy, C₃₋₇cycloalkoxy,C₃₋₇cycloalkylC₁₋₄alkoxy, cyano, NR^(a)R^(b), SR^(a), OSO₂R^(a), or R¹together with the group R² form a 5-membered saturated ring containingone oxygen atom.

A particularly preferred class of compound of formula (I) is thatwherein R¹ is C₁₋₆alkyl, fluoroC₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkoxy,C₃₋₇cycloalkoxy or C₃₋₇cycloalkoxyC₁₋₄alkyl, especially methyl,trifluoromethyl, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, cyclopropoxy or cyclopropylmethoxy.

Another preferred class of compound of formula (I) is that wherein R² isa hydrogen, fluorine or chlorine atom, especially a hydrogen atom.

A further preferred class of compound of formula (I) is that wherein R³is hydrogen, halogen, fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, cyano,NR^(a)R^(b), NR^(a)COR^(d) (where R^(d) is methyl, methoxy,trifluoromethyl or phenyl), or a 5-membered aromatic heterocyclic groupas previously defined.

Also preferred is the class of compound of formula (I) in which R³ isC₁₋₆alkyl, fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy or a 5-membered aromaticheterocyclic group as previously defined, especially methyl,trifluoromethyl, trifluoromethoxy or5-trifluoromethyl-1,2,3,4-tetrazol-1-yl.

Certain particularly apt compounds of the present invention includethose wherein R³ is a group selected from pyrrole, furan, thiene,pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole,isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole,thiadiazole, triazine, and tetrazole, each heteroaryl group beingoptionally substituted as previously defined.

Preferred compounds of the present invention are those wherein R³ is agroup selected from furan, pyridine, pyrazole, imidazole, oxazole,isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole,1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, eachhetero group being optionally substituted as previously defined.

Particularly preferred compounds of the present invention are thosewherein R³ is a group selected from furan, pyridine, pyrimidine,1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl groupbeing optionally substituted as previously defined.

An especially preferred class of compound of formula (I) is that whereinR³ is the group

where R²² is hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, CF₃, OCF₃, NO₂,CN, SR^(a), SOR^(a), SO₂R^(a), COR^(a), CO₂R^(a),(CH₂)_(r)CONR^(a)R^(b), (CH₂)_(r)NR^(a)R^(b) or (CH₂)_(r)NR^(a)COR^(b),where R^(a), R^(b) and r are as previously defined.

R²² is preferably hydrogen, C₁₋₄alkyl, especially methyl, CF₃,(CH₂)_(r)CONR^(a)R^(b), SOR^(a) or SO₂R^(a) where R^(a) and R^(b) arepreferably hydrogen, C₁₋₄alkyl or fluoroC₁₋₄alkyl and r is as previouslydefined. Most especially, R²² is CF₃.

Preferably R¹ and R³ are in the 3 and 5 positions of the phenyl ring.

More preferably R¹ is 3-fluoro or 3-CF₃.

More preferably R³ is 5-fluoro or 5-CF₃.

More preferably R² is hydrogen.

Most preferably R¹ is 3-CF₃, R² is hydrogen and R³ is 5-CF₃.

Another preferred class of compounds of formula (I) is that wherein R¹and R³ are in the 2- and 5-positions of the phenyl ring.

In this sub-class of compounds of formula (I), R¹ is preferablyC₁₋₆alkoxy or C₃₋₇cycloalkoxy, especially methoxy or cyclopropoxy.

Also in this sub-class of compounds of formula (I), R² is preferablyhydrogen.

Also, in this sub-class of compounds of formula (I) R³ is preferablyhydrogen, C₁₋₆alkoxy, fluoroC₁₋₆alkoxy or a 5-membered aromaticheterocyclic group as previously defined. Most especially, R³ ishydrogen, methoxy or trifluoromethoxy.

A further preferred class of compound of formula (I) is that wherein R⁴is hydrogen.

Another preferred class of compounds of formula (I) is that wherein R⁵is hydrogen, fluorine, chlorine or CF₃, especially hydrogen or fluorine.

Preferably R⁴ is hydrogen and R⁵ is hydrogen or 4-fluoro.

Another further preferred class of compounds of formula (I) is thatwherein R⁶ is hydrogen.

A further preferred class of compounds of formula (I) is that wherein R⁷is hydroxy, —(CH₂)_(n)NR⁸R⁹, a C-linked heterocyclyl group or R⁶ and R⁷together represent ═O, —O(CH₂)_(m)O— or —CH₂OCH₂C(O)—.

Another preferred class of compounds of formula (I) is that wherein R⁷is hydroxy or —(CH₂)_(n)NR⁸R⁹, or R⁶ and R⁷ together represent ═O,—O(CH₂)_(m)O— or —CH₂OCH₂C(O)—.

A further preferred class of compounds of formula (I) is that wherein R⁸represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, hydroxyC₁₋₆alkyl,(CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl,C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)aryl, C(O)(CH₂)_(q)heterocyclyl,C(O)(CH₂)_(p)NR^(a)R^(b), (CH₂)_(q)CO₂C₁₋₆alkyl, (CH₂)_(p)NR^(a)CO₂R^(b)or (CH₂)_(q)CONR^(a)aryl;

and R⁹ represents hydrogen, C₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl orCO₂C₁₋₆alkyl;

or R⁸ and R⁹ together with the nitrogen atom to which they are attachedrepresent a heteroaliphatic ring selected from the group consisting of

A yet further preferred class of compounds of formula (I) is thatwherein R⁸ represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,(CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl,C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)aryl, C(O)(CH₂)_(q)heterocyclyl,C(O)(CH₂)_(p)NR^(a)R^(b), (CH₂)_(q)CO₂C₁₋₆alkyl or(CH₂)_(p)NR^(a)CO₂R^(b);

and R⁹ represents hydrogen, C₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl orCO₂C₁₋₆alkyl;

or R⁸ and R⁹ together with the nitrogen atom to which they are attachedrepresent a heteroaliphatic ring selected from the group consisting of

A further preferred class of compounds of formula (I) is that whereinR¹⁰ represents hydrogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,hydroxyC₁₋₆alkyl, fluoroC₁₋₆alkyl, (C₂₋₆alkynyl)aryl, (CH₂)_(q)aryl,(CH₂)_(q)heterocyclyl, (CH₂)_(q)NR^(a)R^(b), OC(O)C₁₋₆alkyl,C(O)(CH₂)_(q)NR^(a)R^(b), CO₂H or —CO₂C₁₋₆alkyl;

and R¹¹ represents hydrogen, halogen, hydroxy, C₁₋₆alkyl or(CH₂)_(q)NR^(a)R^(b);

or when they are attached to the same carbon atom, R¹⁰ and R¹¹ maytogether represent ═O, —O(CH₂)_(m)O—, —CH₂O(CH₂)_(s)—, —CH₂OCH₂C(O)—,—CH₂OCH₂CH(OH)—, —CH₂OCH₂C(CH₃)₂—, —CH₂OC(CH₃)₂CH₂—, —C(CH₃)₂OCH₂CH₂—,—CH₂C(O)OCH₂—, —OC(O)CH₂CH₂—, —C(O)OCH₂CH₂—, —C(O)OC(CH₃)₂CH₂—,—C(O)OCH₂C(CH₃)₂—, —OCH₂(CH₂)_(s)—, —OC(CH₃)₂CH₂CH₂—, —OCH₂CH═CHCH₂—,—OCH₂CH(OH)CH₂CH₂—, —OCH₂CH₂CH(OH)CH₂—, —OCH₂C(O)CH₂CH₂—, or a group ofthe formula

or, when they are attached to adjacent carbon atoms, R¹⁰ and R¹¹ maytogether represent —OCH₂CH₂— or —OCH₂CH(OH)—, or R¹⁰ and R¹¹ maytogether form a fused benzene ring;

or R¹⁰ and R¹¹ together form a C₁₋₂alkylene bridge across thepyrrolidine or piperidine ring to which they are attached.

Another preferred class of compounds of formula (I) is that wherein R¹⁰represents hydrogen, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,hydroxyC₁₋₆alkyl, (C₂₋₆alkynyl)aryl, (CH₂)_(q)aryl,(CH₂)_(q)heterocyclyl, (CH₂)_(q)NR^(a)R^(b), OC(O)C₁₋₆alkyl,C(O)(CH₂)_(q)NR^(a)R^(b), CO₂H or CO₂C₁₋₆alkyl;

and R¹¹ represents hydrogen, halogen, hydroxy, C₁₋₆alkyl or(CH₂)_(q)NR^(a)R^(b);

or when they are attached to the same carbon atom, R¹⁰ and R¹¹ togetherrepresent ═O or —O(CH₂)_(m)O—;

or, when they are attached to adjacent carbon atoms, R¹⁰ and R¹¹together form a fused benzene ring;

or R¹⁰ and R¹¹ together form a C₁₋₂alkylene bridge across thepyrrolidine or piperidine ring to which they are attached.

A further preferred class of compounds of formula (I) is that whereinR¹² represents hydrogen, C₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl,(CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl, CHO, C(O)C₁₋₆alkyl,C(O)C₃₋₇cycloalkyl, C(O)(CH₂)_(q)aryl or CO₂C₁₋₆alkyl.

A yet further preferred class of compounds of formula (I) is thatwherein R⁹ represents hydrogen, C₁₋₆alkyl, (CH₂)_(q)C₃₋₇cycloalkyl orCO₂C₁₋₆alkyl.

A particularly preferred class of compounds of formula (I) is thatwherein R⁸ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl, C₃₋₇cycloalkyl,CH₂C₃₋₇cycloalkyl, (CH₂)_(q)phenyl, (CH₂)_(q)furyl, (CH₂)_(q)pyridyl,(CH₂)_(q)triazolinone, C(O)C₁₋₄alkyl, C(O)(CH₂)_(q)phenyl,C(O)(CH₂)_(q)imidazolyl, C(O)(CH₂)_(q)tetrazolyl, C(O)(CH₂)pyrrolidinyl,C(O)(CH₂)_(p)NR^(a)R^(b), CH₂C(O)C₁₋₄alkyl or(CH₂)_(p)NR^(a)CO₂C₁₋₄alkyl;

and R⁹ represents hydrogen, C₁₋₆alkyl, CH₂C₃₋₅cycloalkyl orCO₂C₁₋₄alkyl;

or R⁸ and R⁹ together with the nitrogen atom to which they are attachedrepresent a heteroaliphatic ring selected from the group consisting of:

A further particularly preferred class of compounds of formula (I) isthat wherein:

R¹⁰ represents hydrogen, hydroxy, methyl, allyl, acetylene,hydroxyC₁₋₄alkyl, —C≡C(phenyl), phenyl, 4-fluorophenyl, CH₂phenyl,CH₂CH₂phenyl, heterocyclyl (wherein said heterocyclyl is selected fromthe group consisting of pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, and hexamethyleneimine, wherein each ringis optionally substituted by one or two groups selected from methyl,hydroxymethyl, cyclohexyl, dimethylamino and benzisothiazole or there isoptionally a benzene ring fused to the ring, or there is optionallypresent a —CH₂CH₂— bridge across the ring), NR^(a)R^(b), OC(O)CH₃,C(O)NR^(a)R^(b), CO₂H or CO₂C₁₋₄alkyl; and

R¹¹ represents hydrogen, fluorine, hydroxy, methyl or dimethylamino;

or, when they are attached to the same carbon atom, R¹⁰ and R¹¹ togetherrepresent ═O or —OCH₂CH₂O—;

or, when they are attached to adjacent carbon atoms, R¹⁰ and R¹¹together form a fused benzene ring;

or, R¹⁰ and R¹¹ together form a —CH₂CH₂— bridge across the pyrrolidineor piperidine ring to which they are attached.

A yet further particularly preferred class of compounds of formula (I)is that wherein R¹² represents hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl,CH₂C₃₋₆cycloalkyl (especially CH₂cyclopropyl or CH₂cyclohexyl), phenyl,CH₂phenyl, CH₂CH₂phenyl (wherein each of said phenyl groups areoptionally substituted by one or two substituents selected fromfluorine, CF₃ or methoxy), CH₂heterocyclyl (wherein said heterocyclyl isselected from the group consisting of 2-, 3- or 4-pyridine, 2- or3-thiophene, 2- or 3-furan, thiazole, and benzisothiazole), CHO,C(O)C₁₋₄alkyl, C(O)C₃₋₆cycloalkyl (especially C(O)cyclopropyl orC(O)cyclohexyl), C(O)CH₂cycloalkyl (especially C(O)CH₂cyclopropyl orC(O)CH₂cyclohexyl), C(O)CH₂CH₂C₃₋₆cycloalkyl (especiallyC(O)CH₂CH₂cyclohexyl), C(O)phenyl or CO₂C₁₋₄alkyl.

Yet another particularly preferred class of compounds of formula (I) isthat wherein R⁹ represents hydrogen, C₁₋₆alkyl, CH₂C₃₋₅cycloalkyl orCO₂C₁₋₄alkyl.

Another preferred class of compound of formula (I) is that wherein thering A is a phenyl ring.

Particularly preferred compounds of formula (I) are those wherein R⁷represents a group selected from:

wherein

-   R³⁰ represents 4-pyridyl, phenyl, phenyl mono-substituted by    fluorine, chlorine, methyl, methoxy or CO₂methoxy, or phenyl    disubstituted by methyl;-   R³¹ represents C₂₋₄alkyl or (CH₂)_(q)C₃₋₇cycloalkyl, especially    tert-butyl, cyclopropylmethyl or cyclohexyl;-   R³² represents C₁₋₆alkyl, tetrahydropyranyl or benzyl;-   R³³ and R³⁴, which may be attached to the same or different carbon    atoms, each independently represent hydrogen or methyl;-   R³⁵ represents hydroxy or methoxy;-   R³⁶ represents hydroxyC₁₋₄alkyl (especially hydroxymethyl),    C₁₋₄alkoxy (especially methoxy) or hydroxy;-   R³⁷ represents methoxy C₂₋₄alkyl (especially methoxymethyl) or    C₂₋₄alkyl;-   R³⁸ represents hydrogen, oxo (═O), hydroxy, trifluoromethyl,    C₁₋₃alkyl (especially isopropyl) or hydroxyC₁₋₃alkyl (especially    hydroxymethyl or hydroxyethyl);-   R³⁹ represents a ring-forming moiety selected from —OCH₂CH₂O—,    —CH₂OCH₂CH₂—, —CH₂OCH₂CH₂CH₂—, —CH₂OCH₂C(O)—, —CH₂OCH₂CH(OH)—,    —CH₂OC(CH₃)₂CH₂—, —C(CH₃)₂OCH₂CH₂—, —CH₂C(O)OCH₂, —C(O)OCH₂CH₂—,    —C(O)OC(CH₃)₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂CH₂CH₂CH₂—, —OC(CH₃)₂CH₂CH₂,    —OCH₂CH═CHCH₂—, —OCH₂CH(OH)CH₂CH₂—, —OCH₂CH₂CH(OH)CH₂—,    —OCH₂C(O)CH₂CH₂— and a group of the formula

-   R⁴⁰ is hydrogen or hydroxy, especially hydrogen;-   R⁴¹ is C₁₋₃alkyl, especially isopropyl; and-   n is zero, 1 or 2, especially zero.

Further preferred compounds of formula (I) are those wherein R⁷represents a group selected from:

wherein

-   R²⁵ represents hydrogen, methyl or hydroxymethyl;-   R²⁶ represents hydrogen, methyl, hydroxy, methylamino,    dimethylamino, cyclopropylamino, phenyl, or phenyl substituted by    fluorine; and-   R²⁷ represents hydrogen, methyl, hydroxy, methylamino, dimethylamino    or cyclopropylamino.

Another preferred class of compounds of formula (I) is that wherein X isthe linker:

Another preferred class of compounds of formula (I) is that wherein R¹³represents hydrogen, methyl or acetyl. In particular, R¹³ representshydrogen.

A further preferred class of compounds of formula (I) is that whereinone of the groups R¹⁴, R¹⁵, R¹⁶ and R¹⁷ represents hydrogen, hydroxy,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, (CH₂)_(p)NR^(a)R^(b), CHO, C(O)C₁₋₆alkyl orCO₂C₁₋₆alkyl, and the other(s) of the groups R¹⁴, R¹⁵, R¹⁶ and R¹⁷ eachrepresent hydrogen.

A particularly preferred class of compounds of formula (I) is thatwherein one of the groups R¹⁴, R¹⁵, R¹⁶ and R¹⁷ represents methyl orhydroxymethyl, and the other(s) of groups R¹⁴, R¹⁵, R¹⁶ and R¹⁷ eachrepresent hydrogen.

Another preferred class of compounds of formula (I) is that whereinR^(21a) represents hydrogen, fluorine or hydroxy and R^(21b) ishydrogen, or R^(21a) and R^(21b) both represent fluorine or togetherrepresent oxo (═O). In particular, R^(21a) is preferably hydrogen,fluorine or hydroxy and R^(21b) is hydrogen. Most especially, R^(21a)and R^(21b) are preferably both hydrogen.

Most especially, a preferred class of compounds of formula (I) is thatwherein X is the linker:

Another preferred class of compounds of formula (I) is that wherein n iszero.

A further preferred class of compounds of formula (I) is that wherein mis 2.

Another preferred class of compounds of formula (I) is that wherein p is1, 2 or 3, particularly 1 or 2, and especially 1.

A further preferred class of compounds of formula (I) is that wherein qis zero, 1 or 2, particularly zero or 1.

One favoured group of compounds of the present invention are of theformula (Ia) and pharmaceutically acceptable salts thereof:

wherein

A¹ is fluorine or CF₃;

A² is fluorine or CF₃;

A³ is fluorine or hydrogen; and

R⁶ and R⁷ are as defined in relation to formula (I).

When any variable occurs more than one time in formula (I) or formula(Ia) or in any substituent, its definition on each occurrence isindependent of its definition at every other occurrence.

As used herein, the term “alkyl” or “alkoxy” as a group or part of agroup means that the group is straight or branched. Examples of suitablealkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyland t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the term “hydroxyC₁₋₆alkyl” means a C₁₋₆alkyl group inwhich one or more (in particular 1 to 3, and especially 1) hydrogenatoms have been replaced by hydroxy groups. Particularly preferred arehydroxyC₁₋₃alkyl groups, for example, CH₂OH, CH₂CH₂OH, CH(CH₃)OH orC(CH₃)₂H, and most especially CH₂OH.

As used herein, the terms “fluoroC₁₋₆alkyl” and fluoroC₁₋₆alkoxy means aC₁₋₆alkyl or C₁₋₆alkoxy group in which one or more (in particular, 1 to3) hydrogen atoms have been replaced by fluorine atoms. Particularlypreferred are fluoroC₁₋₃alkyl and fluoroC₁₋₆alkoxy groups, for example,CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, OCF₃, OCH₂CH₂F, OCH₂CHF₂ or OCH₂CF₃, andmost especially CF₃, OCF₃ and OCH₂CF₃.

The cycloalkyl groups referred to herein may represent, for example,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable(CH₂)_(q)C₃₋₇cycloalkyl group where q is 1 may be, for example,cyclopropylmethyl or cyclohexylmethyl.

Similarly cycloalkoxy groups referred to herein may represent, forexample, cyclopropoxy or cyclobutoxy.

As used herein, the terms “alkenyl” and “alkynyl” as a group or part ofa group means that the group is straight or branched. Examples ofsuitable alkenyl groups include vinyl and allyl. A suitable alkynylgroup is acetylene or propargyl.

When used herein the term “halogen” means fluorine, chlorine, bromineand iodine. The most apt halogens are fluorine and chlorine of whichfluorine is preferred, unless otherwise stated.

As used herein, the term “aryl” as a group or part of a group means anaromatic radical such as phenyl, biphenyl or naphthyl, wherein saidphenyl, biphenyl or naphthyl group may be optionally substituted by one,two or three groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆alkoxy, fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, NO₂, cyano, SR^(a),SOR^(a), SO₂R^(a), COR^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₄alkoxyC₁₋₄alkyl or —O(CH₂)_(m)O—. Preferably saidphenyl, biphenyl or naphthyl group is optionally substituted by one ortwo substituents, especially none or one. Particularly preferredsubstituents include fluorine, chlorine, bromine, C₁₋₄alkyl (especiallymethyl), C₁₋₄alkoxy (especially methoxy), trifluoromethyl,trifluoromethoxy or vinyl.

As used herein, the term “heterocyclyl” as a group or part of a groupmeans a saturated, partially saturated or unsaturatedheteroatom-containing ring-shaped radical, where the heteroatoms may beselected from nitrogen, oxygen and sulfur. Examples of saturatedheterocyclyl radicals include N-linked saturated 3 to 6-memberedheteromonocyclic groups containing 1 to 3 nitrogen atoms and optionally1 oxygen or sulfur atom (for example, azetidinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl or piperazinylsubstituted on the nitrogen atom by a C₁₋₄alkyl group or a C₂₋₄alkylgroup substituted by hydroxy or C₁₋₂alkoxy). Examples of saturatedheterocyclyl radicals also include C-linked saturated 3 to 6-memberedheteromonocyclic groups containing, for example, one oxygen atom (forinstance, tetrahydrofuranyl or tetrahydropyranyl). Examples of partiallysaturated heterocyclyl radicals include N-linked partially saturated 3to 6-membered heteromonocyclic groups containing 1 to 3 nitrogen atoms(for example, 3-pyrroline). Examples of unsaturated heterocyclylradicals include heteroaromatic rings selected from pyrrolyl, furanyl,thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl,oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indolyl, benzofuranyl,benzthiophenyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl,benzthiazolyl or benzisothiazolyl.

Said saturated and partially saturated heterocyclyl radicals may beoptionally substituted by one, two or three groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, fluoroC₁₋₆alkyl,fluoroC₁₋₆alkoxy, NO₂, cyano, oxo (═O), NR^(a)R^(b), SR^(a), SOR^(a),SO₂R^(a), COR^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₄alkoxyC₁₋₄alkyl, —O(CH₂)_(m)O—, —OCH₂CH₂CH₂—, —CH₂OCH₂CH₂— or—CH₂OCH₂C(O)—. Preferably said saturated or partially saturatedheterocyclyl radical is optionally substituted by one or twosubstituents, especially none or one. Particularly preferredsubstituents include fluorine, chlorine, bromine, C₁₋₄alkyl (especiallymethyl), C₁₋₄alkoxy (especially methoxy), trifluoromethyl,trifluoromethoxy, oxo, vinyl, C₁₋₄alkylamino (especially methylamino) ordi(C₁₋₄alkyl)amino (especially dimethylamino).

Said unsaturated heterocyclyl radicals may be optionally substituted byone, two or three groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆alkoxy, fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, NO₂, cyano, NR^(a)R^(b),SR^(a), SOR^(a), SO₂R^(a), COR^(a), CO₂R^(a), CONR^(a)R^(b),C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₄alkoxyC₁₋₄alkyl or —O(CH₂)_(m)O—.Preferably said unsaturated heterocyclyl is optionally substituted byone or two substituents, especially none or one. Particularly preferredsubstituents include fluorine, chlorine, bromine, C₁₋₄alkyl (especiallymethyl), C₁₋₄alkoxy (especially methoxy), trifluoromethyl,trifluoromethoxy or vinyl.

As used herein, the term “carbocyclyl” as a group or part of a groupmeans a 3 to 7-membered cycloalkyl radical such as cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, wherein said cycloalkyl radicalmay be optionally substituted by one, two or three groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkyl,fluoroC₁₋₆alkyl, fluoroC₁₋₆alkoxy, NO₂, cyano, SR^(a), SOR^(a),SO₂R^(a), COR^(a), CO₂R^(a), CONR^(a)R^(b), C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₄alkoxyC₁₋₄alkyl or —O(CH₂)_(m)O—. Preferably said cycloalkyl radicalis substituted by one or two substituents, especially one. Particularlypreferred substituents include fluorine, chlorine, bromine, C₁₋₄alkyl(especially methyl), methoxy, hydroxyC₁₋₄alkyl (especially C(CH₃)₂OH),trifluoromethyl, trifluoromethoxy or vinyl.

Specific compounds within the scope of this invention include:

-   cis-(RS)-α-methyl-N-{4-[4-phenylmethyl-4-(dimethylamino)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-phenylmethyl-4-(dimethylamino)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   cis-(RS)-α-methyl-N-{4-[4-(phenylmethyl)-4-hydroxypiperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-(phenylmethyl)-4-hydroxypiperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethylbenzeneacetamide;-   cis-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-N,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α-hydroxymethyl-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(4-oxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{1-phenyl-4-[(phenylmethyl)amino]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[N-methyl(phenylmethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-(4-methylamino-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-N-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]-N-(phenylmethyl)glycine    methyl ester;-   trans-(RS)-N-methyl-N-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycine    methyl ester;-   trans-(RS)-α-methyl-N-{4-[2-(dimethylamino)acetylamino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-N-(4-aminomethyl-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide,-   trans-(RS)-α-methyl-N-(4-dimethylaminomethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(piperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenyl-N-{2-[3,5-bis(trifluoromethyl)phenyl]propyl}cyclohexylamine;    and pharmaceutically acceptable salts thereof.

Further particularly preferred compounds of the present inventioninclude:

-   cis-(RS)- and    trans-(RS)-α-methyl-N-{4-[4-hydroxymethyl-4-(methoxymethyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethylbenzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(1,4-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(2-oxa-4-oxo-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(2R*,3′R*)- and    trans-(2R*,3′S*)-α-methyl-N-[4-(3-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(2R*,4′R*) and    trans-(2R*,4′S*)-α-methyl-N-[4-(4-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(R,S)-α-methyl-N-[4-(1-oxa-3-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(4-methylpiperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-(1-methylethyl)piperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-(1-methylethyl)-2-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(2,2-dimethyl-4-phenylmethyl-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-(1,1-dimethylethyl)-2-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(S)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-{4-[2-oxo-4-(piperidin-1-yl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(4-oxopiperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide;-   trans-(RS)-α-methyl-N-[4-(4-hydroxypiperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide;-   cis-(RS)-α-methyl-N-[4-hydroxy-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   trans-(RS)-α-methyl-N-[1-phenyl-4-{1-(1-methylethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;-   (1R*,3S*,4R*)- and    (1R*,3R*,4R)-α,α-dimethyl-N-[3-hydroxy-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;-   (1R*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;    and pharmaceutically acceptable salts thereof.

In a further aspect of the present invention, the compounds of formula(I) may be prepared in the form of a pharmaceutically acceptable salt,especially an acid addition salt.

For use in medicine, the salts of the compounds of formula (I) will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts which may, for example, be formed by mixinga solution of the compound according to the invention with a solution ofa pharmaceutically acceptable acid such as hydrochloric acid, fumaricacid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxylic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionality.

The present invention includes within its scope solvates of thecompounds of formula (I) and salts thereof, for example, hydrates.

The compounds according to the invention have one or more asymmetriccentres, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The preferred compounds of the formula (I) and (Ia) will have thestereochemistry of the 1- and 4-positions as shown in formula (Ib)

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula for compounds ofthe present invention as well as to the preferred classes of compoundrepresented by formula (Ia) and formula (Ib).

The present invention further provides pharmaceutical compositionscomprising one or more compounds of formula (I) in association with apharmaceutically acceptable carrier or excipient.

Preferably the compositions according to the invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,solutions or suspensions, or suppositories, for oral, parenteral orrectal administration, or administration by inhalation or insufflation.Oral compositions such as tablets, pills, capsules or wafers areparticularly preferred.

A more detailed description of pharmaceutical compositions that aresuitable for the formulation of compounds of the present invention isdisclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see in particular, column 8, line 50to column 10, line 4).

The present invention further provides a process for the preparation ofa pharmaceutical composition comprising a compound of formula (I), whichprocess comprises bringing a compound of formula (I) into associationwith a pharmaceutically acceptable carrier or excipient.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Acomprehensive listing of clinical conditions, uses and methods oftreatment for which the compounds of the present invention will beuseful is disclosed in U.S. Pat. No. 6,071,927, the content of which isincorporated herein by reference (see, in particular, column 10, line 14to column 22, line 18).

In particular, the compounds of the present invention are useful in thetreatment of a variety of disorders of the central nervous system. Suchdisorders include mood disorders, such as depression or moreparticularly depressive disorders, for example, single episodic orrecurrent major depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder; and anxiety disorders, such as panic disorder withor without agoraphobia, agoraphobia without history of panic disorder,specific phobias, for example, specific animal phobias, social phobias,obsessive-compulsive disorder, stress disorders including post-traumaticstress disorder and acute stress disorder, and generalised anxietydisorders.

The compounds of the present invention are also particularly useful inthe treatment of nociception and pain. Diseases and conditions in whichpain predominates, include soft tissue and peripheral damage, such asacute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletalpain, particularly after trauma, spinal pain, myofascial pain syndromes,headache, migraine, episiotomy pain, and burns.

The compounds of the present invention are also particularly useful inthe treatment of respiratory diseases, particularly those associatedwith excess mucus secretion, such as chronic obstructive airwaysdisease, bronchopneumonia, chronic bronchitis, cystic fibrosis andasthma, adult respiratory distress syndrome, and bronchospasm; in thetreatment of inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritisand sunburn; and in the treatment of allergic disorders such as eczemaand rhinitis.

The compounds of the present invention are also particularly useful inthe treatment of gastrointestinal (GI) disorders, including inflammatorydisorders and diseases of the GI tract such as ulcerative colitis,Crohn's disease and irritable bowel syndrome.

The compounds of the present invention are also particularly useful inthe treatment of emesis, including acute, delayed or anticipatoryemesis, such as emesis induced by chemotherapy, radiation, toxins,pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. Most especially, the compounds offormula (I) are of use in the treatment of emesis induced byantineoplastic (cytotoxic) agents, including those routinely used incancer chemotherapy; by radiation including radiation therapy such as inthe treatment of cancer; and in the treatment of post-operative nauseaand vomiting.

The excellent pharmacological profile of the compounds of the presentinvention offers the opportunity for their use in therapy at low dosesthereby minimising the risk of unwanted side effects.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg per day.

For example, in the treatment of conditions involving theneurotransmission of pain sensations, a suitable dosage level is about0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day,and especially about 0.005 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

In the treatment of emesis, a suitable dosage level is about 0.001 to 10mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially0.01 to 3 mg/kg per day. The compounds may be administered on a regimenof 1 to 4 times per day, preferably once or twice per day.

In the treatment of psychiatric disorders, a suitable dosage level isabout 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg perday, and especially 0.01 to 3 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be appreciated that the amount of a compound of formula (I)required for use in any treatment will vary not only with the particularcompounds or composition selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient, and will ultimately be at the discretionof the attendant physician.

According to a general process (A), compounds of formula (I), in which Xis —N(R¹³)C(O)CR¹⁴R¹⁵—, may be prepared by reaction of a compound offormula (II) with a compound of formula (III) or an activated derivativethereof

in the presence of a base and a coupling reagent.

Suitable bases of use in the reaction include tertiary amines, forexample, triethylamine.

Suitable coupling reagents include any of the coupling reagents commonlyused in peptide synthesis. A preferred coupling reagent is1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).Preferably the coupling reaction is effected in the presence of1-hydroxybenzotrazole hydrate (HOBT).

The reaction is conveniently effected in a suitable organic solvent suchas, for example, dimethylformamide.

According to an alternative general process (B), compounds of formula(I), in which X is —N(R¹³)C(O)CR¹⁴R¹⁵—, may be prepared by the reactionof an amine of formula (II) with an activated carboxylic acid derivativeof formula (IV)

where L is a leaving group.

Suitable activated carboxylic acid derivatives represented in formula(IV) include acyl halides (e.g. acid chlorides) and acid anhydridesincluding mixed anhydrides (e.g. acid formic anhydride). These activatedderivatives may be formed from the corresponding acid of formula (III)by well known procedures. For example, acid chlorides may be prepared byreaction with phosphorus pentachloride, thionyl chloride or oxalylchloride and acid anhydrides may be prepared by reaction with anappropriate acid anhydride (e.g. trifluoroacetic anhydride), an acidchloride (e.g. acetyl chloride), an alkyl or aralkyl haloformate (e.g.ethyl or benzyl chloroformate) or methanesulphonyl chloride.

A particularly preferred reagent for activating the carboxylic acidgroup is bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl).

Activated carboxylic acid derivatives of formula (IV) may also beprepared in situ by reaction of the corresponding acids of formula(III), with a coupling reagent such as carbonyldiimidazole,dicyclohexylcarbodiimide or diphenylphosphorylazide.

The conditions under which the activated carboxylic acid derivatives offormula (IV) are formed and subsequently reacted with the amines offormula (II) will depend upon the nature of the activated derivative.However, in general the reaction between the compounds (II) and (IV) maybe carried out in a non-aqueous medium such as, for example,dimethylformamide, tetrahydrofuran, acetonitrile or a halogenatedhydrocarbon such as dichloromethane at a temperature within the range−25° C. to +150° C. The reaction may optionally be carried out in thepresence of a base such as triethylamine or pyridine and the base mayalso be used as the solvent for reaction.

Where acid chlorides are used, the reaction may be carried out using theSchotten-Baumann technique in the presence of a suitable base, forexample, aqueous sodium hydroxide, conveniently at a temperature between0° C. and 100° C., for example, room temperature.

According to another general process (C), compounds of formula (I), inwhich X is —N(R¹³)CR¹⁴R¹⁵CR¹⁶R¹⁷—, may be prepared by the reaction of acompound of formula (II) with a compound of formula (V)

in the presence of a reducing agent.

Suitable reducing agents for use in this reaction include, for example,sodium cyanoborohydride or sodium triacetoxyborohydride.

The reaction is conveniently effected in a suitable solvent such as ahalogenated hydrocarbon, for example, 1,2-dichloroethane, an alcohol,for example, methanol, acetic acid or a mixture thereof.

According to another general process (D), compounds of formula (I), inwhich X is —OC(O)CR¹⁴R¹⁵—, may be prepared by the reaction of a compoundof formula (VI) with a compound of formula (VII)

in the presence of a base (provided that R^(21a) is not hydroxy).

Suitable bases of use in the reaction include aromatic amines such aspyridine or 4-(dimethylamino)pyridine (DMAP).

The reaction is conveniently effected in a suitable aprotic solvent suchas, for example, dimethylformamide, or a halogenated hydrocarbon, forexample, dichloromethane, or a mixture thereof.

According to another general process (E), compounds of formula (I), inwhich X is —OCR¹⁴R¹⁵CR¹⁶R¹⁷—, may be prepared by the reaction of acompound of formula (VI) with a compound of formula (VIII)

(wherein Hal is a halogen atom such as chlorine, iodine or, preferably,bromine), in the presence of a base such as sodium hydride.

The reaction is conveniently effected in a suitable aprotic solvent suchas, for example, dimethylformamide.

It will be appreciated that compounds of formula (I) may also beprepared from other compounds of formula (I) by a variety ofinterconversion processes.

Thus, according to general process (F.1), compounds of formula (I) inwhich X is —N(R¹³)CR¹⁴R¹⁵CR¹⁶R¹⁷—, may be prepared by theinterconversion of a compound of formula (I) in which X is—N(R¹³)C(O)CR¹⁴R¹⁵—, by reaction with a reducing agent.

Suitable reducing agents for use in this reaction include sodiumborohydride or borane.tetrahydrofuran complex.

The reaction is conveniently effected in a solvent such as an ether, forexample, tetrahydrofuran.

According to another general process (F.2), compounds of formula (I) inwhich R⁷ is —(CH₂)_(n)NR⁸R⁹ (where n is zero) may be prepared byinterconversion of a compound of formula (I) in which R⁶ and R⁷ togetherrepresent ═O, by reaction with an appropriate amine, R⁸R⁹NH, in thepresence of sodium cyanoborohydride and a Lewis acid, for example, zincchloride, in a solvent such as an alcohol, for example, methanol, or inthe presence of sodium triacetoxyborohydride in a solvent such as ahalogenated hydrocarbon, for example, 1,2-dichloroethane.

Yet further interconversion reactions that may be effected usingconventional procedures are shown in the following Scheme 1. The methodsdepicted in Scheme 1 are not exhaustive and illustrate just some of thepossible routes to further compounds of formula (I).

It will be appreciated that reference to R, R′ and R″ in Scheme 1 refersto suitable substituents within the scope of the definitions of formula(I), insofar as said substituents are compatible with the reactionconditions described in Scheme 1.

Preferably, where R^(21a) is halogen or hydroxy, or R^(21a) and R^(21b)both represent fluorine or together represent oxo (═O), suchsubstituents are introduced at a late stage by conventional methodology.It will be appreciated, however, that where such substituents arecompatible with the reactions described above, then such groups may bepresent, even if not depicted in the above formulae.

Further details of suitable procedures for the preparation of compoundsof formula (I) will be found in the accompanying Examples.

Compounds of formula (II) may be prepared by a variety of methods wellknown to those skilled in the art. Examples of suitable methods include,but are not limited to, the methods shown in Scheme 2.

Compounds of formula (III) are either known compounds or may be preparedby a variety of methods well known to those skilled in the art. Examplesof suitable methods for introducing the substituents R¹⁴ and R¹⁵include, but are not limited to, the methods shown in Scheme 3.

Compounds of formula (V) may be prepared by conventional methods such aspartial reduction of a corresponding carboxylic acid of formula (III).

Compounds of formula (VI) may be prepared as shown, for instance, in thefirst step of Scheme 2, above.

Compounds of formula (VII) may be prepared from the correspondingcarboxylic acids of formula (III) using methods analogous to thosedescribed herein for the synthesis of compounds of formula (IV).

Compounds of formula (VIII) are either known compounds or may beprepared by conventional methods, for instance, by methods analogous tothose described herein.

Compounds of formula (I) in which the ring A is a pyridyl ring may beprepared in an analogous manner to the methods described above,replacing the phenyl ring depicted in the above formulae as appropriate.

It will be appreciated that the general methodology described above maybe adapted, using methods that are readily apparent to one of ordinaryskill in the art, in order to prepare further compounds of the presentinvention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The exemplified compounds of this invention were tested by the methodsset out at pages 36 to 39 of International Patent Specification No. WO93/01165. The compounds were found to be active with IC₅₀ at the NK₁receptor of less than 100 nM on said test method.

The following non-limiting Examples serve to illustrate the preparationof compounds of the present invention:

DESCRIPTION 1 Methyl 3,5-Bis(trifluoromethyl)benzeneacetate

Sulfuric acid (conc., 1 mL) was added to a solution of3,5-bis(trifluoromethyl)benzeneacetic acid (50.0 g, 0.18 mol) inmethanol (400 mL) and the mixture was stirred at room temperature for 1week. The solvent was evaporated and ethyl acetate (100 mL) and aqueoussodium hydrogen carbonate (saturated, 600 mL) were added. The layerswere separated and the aqueous layer was extracted with ethyl acetate(2×300 mL). The combined organic fractions were washed with brine, dried(MgSO₄) and the solvent was evaporated under reduced pressure to givethe title compound (49.0 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (1H,s), 7.75 (2H, s), 3.77 (2H, s), and 3.75 (3H, s).

DESCRIPTION 2 Methyl 2-[3,5-Bis(trifluoromethyl)phenyl]-2-propenoate

A mixture of methyl 3,5-bis(trifluoromethyl)benzeneacetate (Description1, 10.0 g, 35 mmol), paraformaldehyde (5.2 g, 175 mmol), potassiumcarbonate (14.5 g, 105 mmol) and tetra-n-butyl ammonium iodide (650 mg,1.75 mmol) in toluene (200 mL) was heated at 80° C. for 4 hours, cooledand stirred at room temperature for 16 hours. The mixture was filteredthrough a bed of Celite™, washing with ethyl acetate (2×100 mL). Thecombined filtrates were washed with water (100 mL) and brine (100 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (100:0 increasing to 90:10) to give thetitle compound as a clear oil (6.2 g, 60%). ¹H NMR (400 MHz, CDCl₃) δ3.86 (3H, s), 6.05 (1H, s), 6.59 (1H, s), 7.86 (1H, s) and 7.88 (2H, s).

DESCRIPTION 3 (RS)-Methylα-Methyl-3,5-bis(trifluoromethyl)benzeneacetate

An aqueous slurry of palladium on carbon (50 mg) was added to a solutionof methyl 2-[3,5-bis(trifluoromethyl)phenyl]-2-propenoate (Description2, 1.0 g, 3.4 mmol) in ethanol (40 mL) and the mixture was shaken underan atmosphere of hydrogen (50 psi) for 1 hour. The mixture was filteredand the solvent was evaporated under reduced pressure to give the titlecompound as a colorless oil (0.97 g, 95%). ¹H NMR (360 MHz, CDCl₃) δ1.57 (3H, d, J 7.2 Hz), 3.71 (3H, s), 3.86 (1H, q, J 7.2 Hz), 7.76 (2H,s) and 7.79 (1H, s).

DESCRIPTION 4 (RS)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetic Acid

Aqueous sodium hydroxide (4M, 3 mL, 12 mmol) was added to a solution of(RS)-methyl α-methyl-3,5-bis(trifluoromethyl)benzeneacetate (Description3, 0.96 g, 3.2 mmol) in methanol (5 mL) and the mixture was heated underreflux for 1 hour. The mixture was cooled and the solvent was evaporatedunder reduced pressure. The residue was diluted with water, acidifiedwith hydrochloric acid (2M) and extracted with ethyl acetate (2×25 mL).The combined organic fractions were washed with brine, dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the titlecompound as a colorless solid (0.92 g, 99%). ¹H NMR (360 MHz, CDCl₃) δ1.60 (3H, d, J 7.2 Hz), 3.90 (1H, q, J 7.2 Hz), 7.78 (2H, s) and 7.81(1H, s).

DESCRIPTION 5 Methyl α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetate

Sodium hydride (60% in mineral oil, 2.1 g, 52.5 mmol) was added inportions to a solution of methyl 3,5-bis(trifluoromethyl)benzeneacetate(Description 1, 5 g, 17.5 mmol) in dimethylformamide (100 mL) and themixture was stirred at room temperature for 10 minutes. Iodomethane(5.45 mL, 87.5 mmol) was added and the mixture was stirred at roomtemperature overnight. Aqueous ammonium chloride (saturated) was addedand the mixture was extracted with ethyl acetate. The combined organicfractions were washed with water, dried (MgSO₄), and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (100:0increasing to 90:10) to give the title compound as a colorless oil (5.34g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 7.78 (3H, s), 3.69 (3H, s), and 1.65(6H, s).

DESCRIPTION 6 α,α-Dimethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid

Lithium hydroxide monohydrate (2.13 g, 50.6 mmol) was added to asuspension of methyl α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetate(Description 5, 5.3 g, 16.88 mmol) in methanol (60 mL), water (20 mL)and tetrahydrofuran (20 mL) and the mixture was degassed and stirred atroom temperature for 3 days. The solvent was evaporated under reducedpressure and the residue was suspended in hydrochloric acid (1M). Themixture was extracted with ethyl acetate and the combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound as a colorless solid (5.05g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 7.84 (2H, s), 7.80 (1H, s), and 1.68(6H, s).

DESCRIPTION 7 (RS)-Methylα-(Hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate

A mixture of methyl 3,5-bis(trifluoromethyl)benzeneacetate (Description1, 10.0 g, 35 mmol), paraformaldehyde (1.15 g, 38.5 mmol) and sodiumhydrogen carbonate (84 mg, 1 mmol) in dimethylsulfoxide (10 mL) washeated at 45° C. for 1 hour, cooled and water (200 mL) was added. Themixture was extracted with ether (2×200 mL) and the combined organicfractions were washed with water (4×100 mL) and brine (100 mL), dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (75:25) to give the title compound as acolorless oil (2.0 g, 10%). ¹H NMR (400 MHz, CDCl₃) δ 2.27 (1H, t, J 7.0Hz), 3.76 (3H, s), 3.94–3.99 (2H, m), 4.01–4.15 (1H, m), 7.77 (2H, s)and 7.83 (1H, s).

DESCRIPTION 8 Lithium(RS)-α-(Hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate

Lithium hydroxide (168 mg, 4 mmol) in water (2 mL) was added to asolution of (RS)-methylα-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description 7,500 mg, 1.6 mmol) in methanol (4 mL). Methanol (2 mL) andtetrahydrofuran (2 mL) were added and the mixture was stirred at roomtemperature for 2 hours. The solvent was evaporated under reducedpressure and the residue was dried azeotropically by evaporating toluene(×2) to to give the crude title compound as a colorless gum (870 mg),which was used without further purification. ¹H NMR (400 MHz, CD₃OD) δ3.73–3.79 (1H, m), 3.85–3.92 (1H, m), 4.02–4.06 (1H, m), 7.80 (1H, s)and 7.98 (2H, s).

DESCRIPTION 9 4-(4-Fluorophenyl)pyridine

A mixture of 4-fluorobenzeneboronic acid (38.7 g, 276 mmol),4-bromopyridine hydrochloride (48.9 g, 250 mmol),[1,4-butanediylbis(diphenylphosphine-κP)] dichloropalladium(Organometallics 1998, 17, 661; 1.52 g, 2.5 mmol), 1,2-dimethoxyethane(500 mL) and sodium carbonate solution (2M, 440 mL) was degassed withbubbling nitrogen and stirred at 80° C. for 24 hours. The mixture wascooled and extracted with ethyl acetate. The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reduced pressureto give crude title compound as a brown solid (50.87 g) which was usedwithout further purification. ¹H NMR (360 MHz, CDCl₃) δ 8.65 (2H, m),7.61 (2H, m), 7.49 (2H, dd, J 1.6, 4.6 Hz), and 7.09 (2H, m).

DESCRIPTION 104-(4-Fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine

Benzyl bromide (52.4 mL, 441 mmol) was added to a solution of4-(4-fluorophenyl)pyridine (Description 9, 50.87 g, 294 mmol) in acetone(500 mL) and mixture was heated under reflux for 3 days. The mixture wascooled to room temperature and the solid was collected, washed withacetone and diethyl ether and dried in vacuo. The solid was dissolved inmethanol (400 mL) and water (100 mL), cooled to 0° C. and sodiumborohydride (20.6 g, 542 mmol) was added in portions. The mixture wasstirred at room temperature for 1 hour, then heated under reflux for 18hours. The mixture was cooled and the solvent was evaporated underreduced pressure. Dichloromethane (300 mL) and water (200 mL) were addedand the layers were separated. The organic layer was dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the titlecompound as a light brown oil (61.5 g, 78%). m/z (ES⁺) 268 (M+1).

DESCRIPTION 11 4-(4-Fluorophenyl)piperidine

Palladium hydroxide on carbon(20%, 5 g) was added to a solution of4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine(Description 10, 60 g, 225 mmol) in methanol (500 mL) and the mixturewas shaken under an atmosphere of hydrogen (50 psi) for 48 hours. Themixture was filtered through a glass fibre pad, washing with methanol,and the solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate and ethereal hydrogen chloride (1M, 300 mL)was added. The solid was collected and recrystallised from 2-propanol togive 4-(4-fluorophenyl)piperidine hydrochloride as a colorless solid(30.5 g, 63%). m/z (ES⁺) 180 (M+1).A sample (1 g, 4.64 mmol) was suspended in ethyl acetate and washed withsaturated aqueous sodium carbonate. The organic layer was dried (MgSO₄)and the solvent was evaporated under reduced pressure to give the titlecompound as a colorless oil (825 mg, 99%). m/z (ES⁺) 180 (M+1).

DESCRIPTION 124-(Dimethylamino)-1-(phenylmethyl)-4-piperidinecarbonitrile

A solution of 1-(phenylmethyl)-4-piperidone (9.46 g, 50 mmol) in ethanol(20 mL) was added slowly to a stirred solution of potassium cyanide(3.58 g, 55 mmol) and dimethylamine hydrochloride (4.89 g, 60 mmol) inwater (60 mL). The mixture was stirred at room temperature for 68 hours,then water (100 mL) was added. The solid was collected, suspended inaqueous sodium hydrogen carbonate (saturated, 100 mL) and water (50 mL)and extracted with dichloromethane (3×100 mL). The combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the the title compound as a cream solid (11.69g, 96%). m/z (ES⁺) 244 (M+1).

DESCRIPTION 13 4-(Dimethylamino-1,4-bis(phenylmethyl)piperidine

A solution of4-(dimethylamino)-1-(phenylmethyl)-4-piperidinecarbonitrile (Description12, 4.86 g, 20 mmol) in ether (75 mL) was added to benzylmagnesiumchloride (1.0M in ether, 100 mL, 100 mmol) and the mixture was heatedunder reflux for 6 hours. The mixture was cooled in ice and hydrochloricacid (1M, 100 mL) was added slowly. The layers were separated and theaqueous layer was extracted with hydrochloric acid (1M, 2×100 mL). Thecombined aqueous layers were washed with ether (100 mL) then adjusted topH 10.0 with aqueous sodium hydroxide (4M). The mixture was extractedwith ether (3×200 mL) and the combined organic fractions were evaporatedunder reduced pressure. Saturated aqueous sodium hydrogen carbonate (100mL) and water (20 mL) were added and the mixture was extracted withdichloromethane (3×100 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was recrystallized from ethanol-water (2:1, 75 mL) to give thetitle compound as a colorless solid (5.15 g, 84%). m/z (ES⁺) 309 (M+1).

DESCRIPTION 14 4-(Dimethylamino)-4-(phenylmethyl)piperidine

A suspension of palladium on carbon (10%, 2 g) was added to a solutionof 4-(dimethylamino)-1,4-bis(phenylmethyl)piperidine (Description 13,4.62 g, 15 mmol) and formic acid (90%, 1.4 mL) in methanol (100 mL).Ammonium formate (4.73 g, 75 mmol) was added and the mixture was stirredat room temperature for 20 hours. The mixture was filtered, washing withmethanol, and the solvent was evaporated under reduced pressure. Ether(40 mL) was added and the mixture was extracted with hydrochloric acid(1M, 3×40 mL). The combined aqueous layers were washed with ether (40mL), adjusted to pH 12.0 with aqueous sodium hydroxide (4M) andextracted with dichloromethane (3×40 mL). The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was triturated with hexane (20 mL) and the solidwas collected and dried in vacuo to give the the title compound as acolorless solid (2.20 g, 67%). m/z (ES⁺) 219 (M+1).

DESCRIPTION 15 1,4-Dioxa-8-phenylspiro[4.5]decan-8-amine

Sodium azide (1.67 g, 25.6 mmol) was added to a stirred, cooled (−5° C.)solution of 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol (Synth. Commun.(1994), 24(6), 799–807, 2.0 g, 8.5 mmol) in chloroform (20 mL) and themixture was stirred at 5° C. for 10 minutes. Trifluoroacetic acid (3.3mL, 42.5 mmol) was added dropwise over 5 minutes and the mixture wasallowed to warm to room temperature and stirred overnight. The mixturewas diluted with water (50 mL) and extracted with ether (2×50 mL). Thecombined organic fractions were washed with water (50 mL), aqueousammonia (1N, 2×50 mL) and brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was dissolved in ether(20 mL) and added dropwise to lithium aluminum hydride (1M in ether, 25mL, 25 mmol). The mixture was stirred at room temperature for 3 hours,then aqueous sodium hydroxide (1M, 3 mL) and water (3 mL) were addedcarefully. The ether was evaporated under reduced pressure, saturatedaqueous sodium hydrogen carbonate was added and the mixture wasextracted with dichloromethane (3×20 mL). The combined organic fractionswere washed with brine, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with EtOAc to give the titlecompound as a brown gum (80 mg, 4%). m/z (ES⁺) 234 (M+1) and 217(M+1-NH₃).

DESCRIPTION 16 Dimethyl 4-Oxo-1-phenyl-1,3-cyclohexanedicarboxylate

Sodium hydride (60% in mineral oil, 35.8 g, 1.49 mol) was washed withhexane to remove the mineral oil, suspended in dimethylformamide (400mL) and cooled to 0° C. Methyl phenyl acetate (42 mL, 0.3 mol) was addedslowly with stirring. Methyl acrylate (59 mL, 0.65 mol) was addeddropwise over 2 hours at 0° C. and the mixture was stirred at roomtemperature overnight. Aqueous ammonium chloride (saturated) was addedand the mixture was extracted with dichloromethane (2×700 mL). Thecombined organic fractions were washed with water (5×500 mL), dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue purified by flash column chromatography on silica gel, elutingwith isohexane/Et₂O (80:20) and the residue was triturated withisohexane-Et₂O (50:50). The solid was collected and dried iii vacuo togive the title compound as colorless crystals (30 g, 35%). ¹H NMR (400MHz, CDCl₃) δ 12.11 (1H, s), 7.36–7.25 (5H, m), 3.81 (3H, s), 3.64 (3H,s), 3.08 (1H, d, J 16.1 Hz), 2.73 (1H, d, J 16.1 Hz), 2.26–2.37 (2H, m),and 2.22–2.17 (2H, m).

DESCRIPTION 17 4-Oxo-1-phenylcyclohexanecarboxylic Acid

Lithium hydroxide monohydrate (11.08 g, 264 mmol) was added to asuspension of dimethyl 4-oxo-1-phenyl-1,3-cyclohexanedicarboxylate(Description 16, 25.5 g, 87.9 mmol) in methanol (250 mL), water (83 mL)and tetrahydrofuran (83 mL) and the mixture was heated under reflux for3 days. The mixture was cooled and the tetrahydrofuran and methanol wereevaporated under reduced pressure. The pH was adjusted to 1 withhydrochloric acid (5M) and the mixture was extracted withdichloromethane. The combined organic fractions were dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the titlecompound as a light yellow solid (19 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ7.50–7.29 (5H, m), 2.29–2.73 (2H, m), 2.62–2.55 (2H, m), 2.47–2.41 (2H,m), and 2.35–2.27 (2H, m).

DESCRIPTION 18 4-Oxo-1-phenylcyclohexylamine Hydrochloride

Diphenylphosphoryl azide (18.8 mL, 23.9 g, 87 mmol) was added to asolution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 17,17.1 g, 78 mmol) and triethylamine (24.4 mL, 17.7 g, 175 mmol) intoluene (260 mL) and the mixture was stirred at 90° C. for 90 minutes.The mixture was cooled, diluted with ethyl acetate (300 mL) and washedwith sodium carbonate (2×250 mL). The combined aqueous fractions wereextracted with ethyl acetate (300 mL) and the combined organic fractionswere washed with brine (250 mL), dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was suspended inhydrochloric acid (5M, 500 mL) and the mixture was heated under refluxfor 2 hours. The mixture was cooled, the solvent was evaporated underreduced pressure and the residue was dried azeotropically by evaporatingtoluene under reduced pressure (4×) to give crude title compound whichwas used without further purification. m/z (ES⁺) 190 (M+1)

DESCRIPTION 19 Methyl 4-Oxo-1-phenylcyclohexanecarboxylate

Acetyl chloride (0.46 mL, 0.50 g, 6.4 mmol) was added to a solution of4-oxo-1-phenylcyclohexanecarboxylic acid (Description 17, 0.94 g, 4.3mmol) in methanol (5 mL) and the mixture was heated under reflux for 20hours. The mixture was cooled, poured into aqueous sodium hydrogencarbonate (saturated, 100 mL) and extracted with ethyl acetate (2×50mL). The combined organic fractions were dried (Na₂SO₄) and the solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (2 mL), acetic acid (6 mL) and water (2 mL) were addedand the mixture was stirred at 45° C. for 2 hours. The mixture wascooled, the solvent was evaporated under reduced pressure and aqueoussodium hydrogen carbonate (saturated, 100 mL) was added. The mixture wasextracted with ethyl acetate (2×50 mL), the combined organic fractionswere dried (Na₂SO₄) and the solvent was evaporated under reducedpressure to give the title compound (0.98 g, 98%). ¹H NMR (250 MHz,CDCl₃) δ 7.45–7.26 (5H, m), 3.72 (3H, s), 2.77 (2H, m), 2.61–2.38 (4H,m), and 2.25 (2H, m).

DESCRIPTION 20 Cis-Methyl4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylate,Cis-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylicAcid, and Trans-Methyl4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylate

A solution of sodium cyanoborohydride (0.93 g, 14.9 mmol) and zincchloride (1.01 g, 7.45 mmol) in methanol (30 mL) was added to a solutionof methyl 4-oxo-1-phenylcyclohexanecarboxylate (Description 19, 3.45 g,14.9 mmol) and 4-(4-fluorophenyl)piperidine (Description 11, 3.2 g, 17.9mmol) in methanol (50 mL) and the mixture was stirred at roomtemperature for 24 hours. The mixture was poured into water andextracted with ethyl acetate. The combined organic fractions were dried(MgSO₄), and the solvent was evaporated under reduced pressure. Theresidue was recrystallized from ethanol to give cis-methyl4-[4-(4-fluorophenyl)piperidin-1-yl]-phenylcylohexanecarboxylate (0.9 g,15%) as a colorless solid. m/z (ES⁺) 396 (M+1).The mother liquors from the recrystallisation were collected and thesolvent was evaporated under reduced pressure. Methanol (20 mL) andhydrochloric acid (6M, 200 mL) were added and the mixture was heatedunder reflux for 3 days. The mixture was cooled and the solvent wasevaporated under reduced pressure. The residue was dissolved in methanol(100 mL) and acetyl chloride (0.77 mL, 10.8 mmol) was added slowly. Themixture was heated under reflux for 6 hours cooled and the solvent wasevaporated under reduced pressure. Ethyl acetate and aqueous sodiumcarbonate (saturated) were added and the layers were separated. Thesolid which formed in the organic layer was collected and dried in vacuoto givecis-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylicacid as a colorless solid (1.2 g, 21%). m/z (ES⁺) 382 (M+1).The mother liquors from the recrystallisation were dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give trans-methyl4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylate as acolorless solid, (1.6 g, 27%) m/z (ES⁺) 396 (M+1).

DESCRIPTION 21Trans-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylicAcid Hydrochloride

Hydrochloric acid (6M, 100 mL) was added to a suspension of tran-smethyl4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylate(Description 20, 1.6 g, 4.05 mmol) in methanol (10 mL) and the mixturewas heated under reflux for 48 hours. The mixture was cooled and thesolvent was evaporated under reduced pressure to give the title compoundas a colorless solid (1.5 g, 89%). m/z (ES⁺) 382 (M+1).

DESCRIPTION 22Trans-4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylamine

Diphenylphosphoryl azide (114 μl, 0.53 mmol) and triethylamine (150 μl,1.06 mmol) were added to a solution oftrans-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexanecarboxylicacid hydrochloride (Description 21, 200 mg, 0.48 mmol) in toluene (5 mL)and the mixture was heated at 90° C. for 2 hours. The mixture was cooledto room temperature, diluted with aqueous sodium carbonate (saturated,40 mL) and extracted with ethyl acetate (2×25 mL). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. Hydrochloric acid (5M, 10 mL) wasadded and the mixture was heated under reflux for 4 hours. The mixturewas cooled and stirred at room temperature overnight. The mixture wasdiluted with water (10 mL) and washed with ethyl acetate (2×20 mL). Theaqueous fraction was carefully basified with aqueous sodium hydroxide(4M) and extracted with ethyl acetate (2×20 mL). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the title compound as a cleargum (121 mg, 72%). m/z (ES⁺) 353 (M+1).

DESCRIPTION 23 Trans-1,1-Dimethylethyl4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylcarbamate

Di-tert-butyl dicarbonate (244 mg, 1.1 mmol) was added to a solution oftrans-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylamine(Description 22, 200 mg, 0.56 mmol) and triethylamine (83 μl, 0.6 mmol)in dichloromethane (3 mL) and the mixture was stirred at roomtemperature for 20 hours. N,N-Dimethylethylenediamine (90 μl, 0.8 mmol)was added and the mixture was stirred for 1 hour. Dichloromethane (10mL) was added and the mixture was washed with aqueous citric acid (10%,2×20 mL) and brine, dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound as a colorless foam (263 mg,100%). ¹H NMR (400 MHz, CDCl₃) δ 1.32 (9H, s), 1.45–160 (4H, m),1.88–1.91 (2H, m), 2.31–2.34 (3H, m), 2.60–2.62 (1H, m), 2.67–2.85 (6H,m), 3.29–3.37 (3×, m), 4.71 (1 h, s), 6.97 (2H, t, J 8.6 Hz), 7.20–7.24(2H, m), 7.28 (1H, t, J 7.2 Hz), 7.38–7.41 (2H, m), 7.49 (2H, d, J 7.8Hz), and 12.31 (1H, s).

DESCRIPTION 24Trans-4-[4-(4-Fluorophenyl)piperidin-1-yl]-N-methyl-1-phenylcyclohexylamine

Lithium aluminum hydride (1M in tetrahydrofuran, 1.2 mL, 1.2 mmol) wasadded to a solution of trans-1,1-dimethylethyl4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylcarbamate(Description 23, 260 mg, 0.56 mmol) in tetrahydrofuran (10 mL) and themixture was heated under reflux for 4 hours. The mixture was cooled inice and water (50 μl), aqueous sodium hydroxide (4M, 150 μl) and water(150 μl) were added. The mixture was filtered through Celite™ and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (60:8:1), to give the title compound as a colorlessoil (150 mg, 71%). m/z (ES⁺) 367 (M+1).

DESCRIPTION 25Trans-4-(4-Oxopiperidin-1-yl)-1-phenylcyclohexanecarboxylic AcidHydrochloride

Sodium acetoxyborohydride (7.0 g, 32.9 mmol) was added to a degassedsolution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 17,5.98 g, 27.4 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (4.32 g, 30.2mmol) in dichloroethane (125 mL) and the mixture was stirred at roomtemperature for 20 hours. The solvent was evaporated under reducedpressure, methanol (120 mL) was added and the mixture was stirred atroom temperature for 1 hour. The mixture was filtered and cooled to 0°C. Acetyl chloride (10 mL) was added slowly and the mixture was heatedunder reflux for 20 hours. The mixture was cooled, filtered and thesolvent was evaporated under reduced pressure. Aqueous sodium carbonate(saturated, 200 mL) was added and the mixture was extracted with ethylacetate (2×200 mL). The combined organic fractions were dried (Na₂SO₄)and the solvent was evaporated under reduced pressure. Hydrochloric acid(5M, 300 mL) was added and the mixture was heated under reflux for 20hours. The mixture was cooled and the solvent was evaporated underreduced pressure to give the title compound (3.36 g, 36%). m/z (ES⁺) 302(M+1).

DESCRIPTION 26Trans-1-(4-Isocyanato-4-phenylcyclohex-1-yl)piperidin-4-one

Diphenylphosphoryl azide (71 μl, 0.33 mmol) was added to a mixture oftrans-4-(4-oxopiperidin-1-yl)-1-phenylcyclohexanecarboxylic acidhydrochloride (Description 25, 100 mg, 0.3 mmol) and triethylamine (92μl, 0.66 mmol) in toluene (5 mL) and the mixture was stirred at roomtemperature for 1 hour, then at 90° C. for 1.5 hours. The mixture wascooled and ethyl acetate (25 mL) and aqueous sodium carbonate (10%, 20mL) were added. The organic layer was washed with aqueous sodiumcarbonate (10%, 20 mL) and the combined aqueous fractions were extractedwith ethyl acetate (25 mL). The combined organic fractions were washedwith brine (25 mL), dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with EtOAc, to give the titlecompound (30 mg, 34%). ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.49 (2H, m),7.42–7.35 (2H, m), 7.31–7.27 (1H, m), 2.84–2.81 (4H, m), 2.59–2.57 (1H,m), 2.48–2.42 (6H, m), and 1.93–1.81 (6H, m).

DESCRIPTION 27 Trans-1-(4-Amino-4-phenylcyclohex-1-yl)piperidin-4-oneDihydrochloride

Trans-1-(4-Isocyanato-4-phenylcyclohex-1-yl)piperidin-4-one (Description26, 30 mg, 0.1 mmol) in hydrochloric acid (5M, 6 mL) was heated underreflux overnight. The solvent was evaporated under reduced pressure togive the title compound (32 mg, 100%). ¹H NMR (400 MHz, CD₃OD) δ7.72–7.70 (2H, m), 7.58–7.54 (2H, m), 7.50–7.46 (1H, m), 3.49–3.36 (3H,m), 3.12–2.95 (4H, m), 2.30 (2H, br d, J 11.4 Hz), 2.12–2.03 (4H, m),1.91–1.95 (2H, m), and 1.56–1.47 (2H, m).

DESCRIPTION 28Cis-(RS)-N-(4-Hydroxy-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium borohydride (0.24 g, 6.3 mmol) in ethanol (10 mL) was addedslowly to a stirred, cooled (−78° C.) solution of(RS)-α-methyl-N-[4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 1.9 g, 4.2 mmol) in ethanol (40 mL) and the mixture wasstirred at −78° C. for 3.5 hours. Hydrochloric acid (1M, 10 mL) wasadded slowly and the mixture was warmed to room temperature. Aqueoussodium hydrogen carbonate (saturated) was added and the ethanol wasevaporated under reduced pressure. Water (20 mL) was added and themixture was extracted with ethyl acetate (2×50 mL). The combined organicfractions were washed with brine (20 mL), dried (MgSO₄) and the solventwas evaporated under reduced pressure to give the title compound as acolorless solid (1.6 g, 86%). ¹H NMR (400 MHz, CD₃OD) δ 1.42–1.60 (5H,m), 1.79–1.88 (4H, m), 2.30–2.34 (1H, m), 2.56–2.61 (1H, m), 3.59–3.66(1H, m), 4.03 (1H, q, J 7.0 Hz), 7.09–7.28 (5H, m), 7.85 (1H, s), 7.92(2H, s) and 8.20 (1H, s).

DESCRIPTION 29Cis-(RS)-N-(4-Methanesulfonyloxy-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide

Methanesulfonyl chloride (0.91 mL, 1.35 g, 11.8 mmol) was added to astirred, cooled (0° C.) solution ofCis-(RS)-N-(4-hydroxy-1-phenylcyclohexyl)α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide (Description 28, 1.8 g, 3.9 mmol) and pyridine (1.6 mL,1.55 g, 19.6 mmol) in dichloromethane (40 mL) and the mixture wasstirred at room temperature for 18 hours. Dichloromethane (50 mL) wasadded and the mixture was washed with aqueous citric acid (10%, 2×50 mL)and aqueous sodium hydroxide (1M, 2×50 mL). The mixture was dried(MgSO₄) and the solvent was evaporated under reduced pressure to givethe title compound as a colorless solid (1.97 g, 94%). ¹H NMR (400 MHz,CD₃OD) δ 1.46 (3H, d, J 7.0 Hz), 1.53–1.65 (1H, m), 1.77–2.00 (4H, m),2.02–2.58 (1H, m), 2.41–245 (1H, m), 2.55–2.58 (1H, m), 4.03 (1H, q, J7.0 Hz), 4.66–4.70 (1H, m), 7.13–7.26 (5H, m), 7.87 (1H, s), 7.92 (2H,s) and 8.25 (1H, s).

DESCRIPTION 30Trans-(RS)-N-(4-Azido-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium azide (0.91 g, 14 mmol) was added to a solution ofcis-(RS)-N-(4-methanesulfonyloxy-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Description 29, 1.5 g, 2.8 mmol) in dimethylformamide and the mixturewas stirred at 90° C. for 19 hours. The mixture was cooled, poured intoaqueous ammonium chloride (saturated, 50 mL) and water (50 mL) andextracted with ethyl acetate (2×50 mL). The combined organic fractionswere washed with water (3×50 mL) and brine (50 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the crudetitle compound (1.9 g) which was used without further purification. m/z(ES⁺) 484 (M+1).

DESCRIPTION 31Trans-(RS)-N-(4-Cyano-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide

Tetrabutylammonium cyanide (750 mg, 2.8 mmol) was dried azeotropicallyby evaporating toluene under reduced pressure, then a solution of Cis(RS)-N-(4-methanesulfonyloxy-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Description 29, 250 mg, 0.46 mmol) in toluene (25 mL) was added and themixture was stirred at 70° C. for 24 hours. The mixture was cooled,poured into water (75 mL) and extracted with ethyl acetate (75 mL). Thelayers were separated and the organic layer was washed with brine (50mL), dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with isohexane/EtOAc (80:20), to give the titlecompound (146 mg, 70%). ¹H NMR (400 MHz, CD₃OD) δ 1.46 (3H, d, J 7.2Hz), 1.67–1.83 (4H, m), 2.16–2.20 (2H, m), 2.37–2.49 (2H, m), 2.80–2.84(1H, m), 3.61–3.65 (1H, m), 5.56 (1H, br s), 7.23–7.30 (5H, m), 7.71(2H, s), and 7.79 (1H, s).

DESCRIPTION 32 Dicyclohexylammonium(RS)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetate

n-Butyllithium (2.5M solution in hexanes, 67.6 mL, 169 mmol) was addedslowly to a stirred, cooled (−78° C.) solution of3,5-bis(trifluoromethyl)benzeneacetic acid (20.0 g, 73.5 mmol) intetrahydrofuran (400 mL) and the mixture was stirred at −78° C. for 1hour. Iodomethane (6.87 mL, 110 mmol) was added slowly and the mixturewas allowed to warm to room temperature and stirred overnight. Aqueoussodium bisulfite (20%) was added until the mixture was acidic. Themixture was extracted with ethyl acetate, the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate (400 mL),dicyclohexylamine (10 mL, 80.85 mmol) was added and the mixture washeated under reflux for 1 hour. The mixture was cooled and the solid wascollected and dried in vacuo to give the title compound as a colorlesssolid (31.13 g, 91%). ¹H NMR (400 MHz, CDCl₃) δ 7.83 (2H, s), 7.68 (1H,s), 3.66 (1H, q, J 7.1 Hz), 2.83–2.75 (2H, m), 1.87–1.84 (4H, m),1.71–1.68 (4H, m), 1.60–1.57 (2H, m), 1.48 (3H, d, J 7.1 Hz), 1.28–1.08(8H, m), and 1.03–0.92 (2H, m).

DESCRIPTION 33 (RS)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetic Acid

Dicyclohexylammonium(RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetate (Description 32,31.13 g, 67 mmol) was suspended in ethyl acetate, washed with aqueouscitric acid (25%) and water, dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the title compound as acolorless solid (19.0 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 7.81 (1H, s),7.78 (2H, s), 3.90 (1H, q, J 7.2 Hz), and 1.60 (3H, d, J 7.2 Hz).

DESCRIPTION 34 Dicyclohexylammonium(RS)-α-(2-Propenyl)-3,5-bis(trifluoromethyl)benzeneacetate

Prepared from 3,5-bis(trifluoromethyl)benzeneacetic acid and3-bromo-1-propene according to the method of Description 32. ¹H NMR (400MHz, CD₃OD) δ 7.95 (2H, s), 7.75 (1H, s), 5.82–5.70 (1H, m), 5.01 (1H,br d, J 17 Hz), 4.93 (1H, br d, J 10 Hz), 3.65 (1H, t, J 7 Hz),3.20–3.10 (2H, m), 2.87–2.77 (1H, m), 2.53–2.43 (1H, m), 2.10–2.00 (4H,m), 1.90–1.80 (4H, m), 1.75–1.65 (2H, m), and 1.45–1.12 (10H, m).

DESCRIPTION 35 (RS)-α-(2-Propenyl)-3,5-bis(trifluoromethyl)benzeneaceticAcid

Prepared from dicyclohexylammonium(RS)-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description34) according to the method of Description 33. ¹H NMR (400 MHz, CDCl₃) δ7.81 (1H, s), 7.78 (2H, s), 5.68 (1H, m), 5.15–5.05 (2H, m), 3.82 (1H,t, J 7.6 Hz), 2.90 (1H, ddd, J 14, 7, 7 Hz), and 2.58 (1H, ddd, J 14, 7,7 Hz).

DESCRIPTION 36(4S)3-[3,5-Bis(trifluoromethyl)benzeneacetyl]-4-(phenylmethyl)-2-oxazolidinone

Sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 52.4 mL) wasadded dropwise to a stirred, cooled (−30° C.) solution of(S)-4-(phenylmethyl)-2-oxazolidinone (9.27 g, 52.4 mmol) intetrahydrofuran (150 mL) and the mixture was allowed to warm to 0° C.and stirred for 1 hour. The mixture was added via cannula to a stirred,cooled (−30° C.) solution of freshly prepared3,5-bis(trifluoromethyl)benzeneacetyl chloride (prepared from[3,5-bis(trifluoromethyl)phenyl]acetic acid (15 g, 55.1 mmol), oxalylchloride (9.63 mL, 110.3 mmol) and dimethylformamide (2 drops) indichloromethane (150 mL), followed by evaporation of solvent underreduced pressure) in tetrahydrofuran (100 mL). The mixture was stirredat −30° C. for 1 hour, then allowed to warm slowly to room temperatureand stirred overnight. Hydrochloric acid (1M) was added and the mixturewas extracted with ethyl acetate. The combined organic fractions weredried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane:EtOAc (80:20), to give the title compound as acolorless oil, (9.0 g, 40%). ¹H NMR (360 MHz, CDCl₃) δ 7.83 (1H, s),7.79 (2H, s), 7.34–7.23 (3H, m), 7.18–7.14 (2H, m), 4.74–4.68 (1H, m),4.49–4.37 (2H, m), 4.29–4.21 (2H, m), 3.29 (1H, dd, J 34, 13.4 Hz), and2.80 (1H, dd, J 9.5, 13.4 Hz).

DESCRIPTION 37(4R)-3-[3,5-Bis(trifluoromethyl)benzeneacetyl]-4-phenylmethyl)-2-oxazolidinone

Prepared from (R)-4-(phenylmethyl)-2-oxazolidinone and3,5-bis(trifluoromethyl)benzeneacetyl chloride according to the methodof Description 36. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (1H s), 7.79 (2H, s),7.33–7.26 (3H, m), 7.17–7.15 (2H, m), 4.73–4.69 (1H, m), 4.48–4.37 (2H,m), 4.29–4.22 (2H, m), 3.29 (1H, dd, J 3.4, 13.4 Hz), and 2.80 (1H, dd,J 9.5, 13.4 Hz).

DESCRIPTION 38(4S)-3-{(2S)-1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}-4-(phenylmethyl)-2-oxazolidinone

Sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 19.3 mL) wasadded slowly to a stirred, cooled (−78° C.) solution of(4S)-3-[3,5-bis(trifluoromethyl)benzeneacetyl]-4-(phenylmethyl)-2-oxazolidinone(Description 36, 7.25 g, 16.8 mmol) in tetrahydrofuran (60 mL) and themixture was stirred at −78° C. for 1 hour. Iodomethane (21 mL, 33.6mmol) was added and the mixture was stirred at −78° C. for 30 minutes,at 0° C. for 1 hour, then at room temperature overnight. Saturatedaqueous ammonium chloride was added and the mixture was extracted withethyl acetate. The combined organic fractions were dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting withisohexane:EtOAc (90:10 increasing to 85:15), to give the title compoundas a colorless oil (5.14 g, 69%). ¹H NMR (360 MHz, CDCl₃) δ 7.84 (2H,s), 7.78 (1H, s), 7.38–7.27 (3H, m), 7.23–7.21 (2H, m), 5.26 (1H, q, J7.0 Hz), 4.68–4.64 (1H, m), 4.19–4.15 (2H, m), 3.34 (1H, dd, J 3.3, 13.3Hz), 2.83 (1H, dd, J 9.5, 13.3 Hz), and 1.60 (3H, d, J 7.0 Hz).

DESCRIPTION 39(4R)-3-{(2R)-1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}-4-(phenylmethyl)-2-oxazolidinone

Prepared from(4R)-3-[3,5-bis(trifluoromethyl)benzeneacetyl]-4-phenylmethyl)-2-oxazolidinone(Description 37) according to the method of Description 38. ¹H NMR (400MHz, CDCl₃) δ 7.84 (2H, s), 7.78 (1H, s), 7.37–7.28 (3H, m), 7.23–7.21(2H, m), 5.26 (1H, q, J 7.0 Hz), 4.68–4.64 (1H, m), 4.19–4.16 (2H, m),3.34 (1H, dd, J 3.3, 13.3 Hz), 2.83 (1H, dd, J 9.5, 13.3 Hz), and 1.60(3H, d, J 7.0 Hz).

DESCRIPTION 40 (S)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetic Acid

Aqueous hydrogen peroxide (30%, 14 mL) then lithium hydroxidemonohydrate (944 mg, 22.4 mmol) were added to a stirred, degassed,cooled (0° C.) solution of(4S)-3-{(2S)-1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}-4-(phenylmethyl)-2-oxazolidinone(Description 38, 5.0 g, 11.2 mmol) in tetrahydrofuran/water (4:1, 50 mL)and the mixture was stirred at 0° C. for 2.5 hours. Aqueous sodiumbisulfite (10%) was added slowly, maintaining the internal temperaturebelow 5° C., until the mixture was acidic. The mixture was extractedwith ethyl acetate, the combined organic fractions were dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue wastriturated with isohexane and filtered, washing with isohexane. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in ethyl acetate (10 mL/g) and heated to reflux.Dicyclohexylamine (2.45 mL, 12.3 mmol) was added and the mixture wascooled. The solid was collected, suspended in ethyl acetate and washedwith aqueous citric acid (10%). The organic layer was washed with water,dried (MgSO₄) and the solvent was evaporated under reduced pressure togive the title compound as a colorless solid (1.7 g, 53%). ¹H NMR (400MHz, CDCl₃) δ 7.81 (1H, s), 7.78 (2H, s), 3.90 (1H, q, J 7.2 Hz), and1.60 (3H, d, J 7.2 Hz). e.e. (determined by 500 MHz, ¹H NMR of a mixtureof 140 mmol of acid and 70 mmol of(1R,2R)-1,2-diphenyl-1,2-ethanediamine, at 284K in CDCl₃)>99%.

DESCRIPTION 41 (R)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetic Acid

Prepared from(4R)-3-{(2R)-1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}-4-(phenylmethyl)-2-oxazolidinone(Description 39) according to the method of Description 38. ¹H NMR (400MHz, CDCl₃) δ 7.81 (1H, s), 7.78 (2H, s), 3.90 (1H, q, J 7.2 Hz), and1.60 (3H, d, J 7.2 Hz). e.e (determined by 500 MHz ¹H NMR of a mixtureof 140 mmol of acid and 70 mmol of(1R,2R)-1,2-diphenyl-1,2-ethanediamine, at 284K in CDCl₃) 98.6%.

DESCRIPTION 42 Methyl α,α-Diethyl-3,5-bis(trifluoromethyl)benzeneacetate

Prepared from methyl 3,5-bis(trifluoromethyl)benzeneacetate(Description 1) and iodoethane according to the method of Description 5.¹H NMR (400 MHz, CDCl₃) δ 0.76 (6H, t, J 7.4 Hz), 2.08–2.16 (4H, m),3.69 (3H, s), 770 (2H, s), and 777 (1H, s).

DESCRIPTION 43 Methyl1-[3,5-Bis(trifluoromethyl)phenyl]cyclopropanecarboxylate

Prepared from methyl 3,5-bis(trifluoromethyl)benzeneacetate(Description 1) and 1,2-dibromoethane according to the method ofDescription 5. ¹H NMR (400 MHz, CDCl₃) δ 1.25 (2H, m), 1.73 (2H, m),3.65 (3H, s), and 7.79 (3H, s).

DESCRIPTION 44 α,α-Diethyl-3,5-bis(trifluoromethyl)benzeneacetic Acid

Prepared from methyl α,α-diethyl-3,5-bis(trifluoromethyl)benzeneacetate(Description 42) according to the method of Description 6. ¹H NMR (400MHz, CDCl₃) δ 0.80 (6H, t, J 7.4 Hz), 2.03–2.19 (4H, m), 7.77 (2H, s),and 7.79 (1H, s).

DESCRIPTION 45 1-[3,5-Bis(trifluoromethyl)phenyl]cyclopropanecarboxylicAcid

Prepared from methyl α,α-diethyl-3,5-bis(trifluoromethyl)benzeneacetate(Description 43) according to the method of Description 6. ¹ H NMR (400,CDCl₃) δ 1.32–1.35 (2H, m), 1.78–1.81 (2H, m), and 7.79 (3H, s).

DESCRIPTION 46 (RS)-Methylα-(Methoxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate

(Diazomethyl)trimethylsilane (1.6 mL, 3.2 mmol) was added dropwise to astirred, cooled (0° C.) mixture of (RS)-methylα-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description 7,1.0 g, 3.2 mmol) and aqueous fluoroboric acid (48%, 585 mg, 3.2 mmol) indichloromethane (10 mL) and the mixture was stirred at room temperaturefor 20 minutes. Further (diazomethyl)trimethylsilane (0.8 mL, 1.6 mmol)was added and the mixture was stirred at room temperature for 20minutes. Further (diazomethyl)trimethylsilane (0.4 mL, 0.8 mmol)) wasadded and the mixture was stirred at room temperature for 20 minutes.Further (diazomethyl)trimethylsilane (0.4 mL, 0.8 mmol)) was added andthe mixture was stirred at room temperature for 30 minutes, poured intowater (40 mL) and extracted with dichloromethane (2×40 mL). The combinedorganic fractions were dried (MgSO₄), the solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with isohexane/EtOAc (90:10), togive the title compound as a colorless oil (834 mg, 80%). ¹H NMR (400MHz, CDCl₃) δ 3.36 (3H, s), 3.69–3.73 (1H, m), 3.74 (3H, s), 3.92–3.96(1H, m), 3.99–4.03 (1H, m), and 7.80–7.81 (3H, m).

DESCRIPTION 47(RS)-α-(Methoxymethyl)-3,5-bis(trifluoroethyl)benzeneacetic Acid

Aqueous sodium hydroxide (4 MHz, 1 mL, 4 mmol) was added to a solutionof (RS)-methyl α-(methoxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate(Description 46, 834 mg, 2.5 mmol) in methanol (4 mL) and the mixturewas stirred at room temperature for 20 hours. The solvent was evaporatedunder reduced pressure and the mixture was acidified with hydrochloricacid (1M). The mixture was extracted with dichloromethane (2×20 mL), thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH (95:5), togive the title compound as a colorless oil (126 mg 16%) ¹H NMR (400 MHz,CDCl₃) δ 3.39 (3H, s), 3.71–3.77 (1H, m), 3.92–3.96 (1H, m), 4.02–4.05(1H, m), and 7.78–7.83 (3H, m).

DESCRIPTION 48 3,5-Bis(trifluoromethyl)-α-oxobenzeneacetic Acid

A mixture of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone (3.84 g, 15mmol) and selenium (IV) oxide (2.50 g, 22.5 mmol) in pyridine (25 mL)was stirred at 100° C. for 2 hours, filtered, cooled and the solvent wasevaporated under reduced pressure. Hydrochloric acid (2M, 50 mL) wasadded and the mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic fractions were washed with hydrochloric acid (2M, 50mL) and brine (50 mL), dried (MgSO₄) and the solvent was evaporatedunder reduced pressure to give an orange solid (4.19 g). The residue wasdissolved in propan-2-ol (50 mL) and dicyclohexylamine (2.92 mL, 2.66 g,14.6 mmol) was added. The solvent was evaporated under reduced pressureand the residue was recrystallised from ethanol-water (1:1, 60 mL). Thesolid was collected, suspended in ether (50 mL) and the mixture wasextracted with aqueous sodium hydroxide (1M, 3×25 mL). The combinedaqueous fractions were washed with ether (2×25 mL) and hydrochloric acid(5M, 25 mL) was added. The mixture was extracted with dichloromethane(3×50 mL) and the combined organic fractions were dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue wastriturated with isohexane (40 mL) and the solid was collected and driedin vacuo to give the title compound as a tan solid (1.32 g, 31%). m/z(ES⁻) 285 (M−1).

DESCRIPTION 49 1,1-Dimethylethyl 4-Methoxy-1-piperidinecarboxylate

Sodium hydride (60% dispersion in mineral oil, 2.98 g, 74.5 mmol) wasadded to a solution of 1,1-dimethylethyl4-hydroxy-1-piperidinecarboxylate (5.0 g, 24.8 mmol) indimethylformamide (30 mL) and the mixture was stirred for 5 minutes.Methyl iodide (4.64 mL, 74.5 mmol) was added and the mixture was stirredfor 30 minutes. Water (50 mL) was added and the mixture was extractedwith diethyl ether (2×50 mL). The combined organic fractions were washedwith water (4×50 mL) and brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the title compound (5.3 g,99%). m/z (ES⁺) 216 (M+1).

DESCRIPTION 50 4-Methoxypiperidine

Prepared from 1,1-dimethylethyl 4-methoxy-1-piperidinecarboxylate(Description 49) according to the method of Description 75. ¹H NMR (360MHz, CDCl₃) δ 3.35 (3H, s), 3.29–3.23 (1H, m), 3.11–3.05 (2H, m),2.64–2.57 (2H, m), 1.96–1.90 (2H, m), and 1.46–1.36 (2H, m).

DESCRIPTION 51 1,1-Dimethylethyl4-Ethyl-4-hydroxy-1-piperidinecarboxylate

1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (10.1 g, 50.7 mmol) intetrahydrofuran (40 mL) was added dropwise over 30 minutes to a stirred,cooled (0° C.) solution of ethyl magnesium bromide (1.0M intetrahydrofuran, 50.7 mL, 50.7 mmol) in tetrahydrofuran (30 mL). Themixture was allowed to warm to room temperature and stirred for 4 hours.The mixture was poured into saturated aqueous ammonium chloride (150 mL)and extracted with ethyl acetate (2×150 mL). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with 3:1 isohexane:ethylacetate, to give the title compound (8.5 g, 73%). m/z (ES⁺) 230 (M+1).

DESCRIPTION 52 1,1-Dimethylethyl4-Ethyl-4-methoxy-1-piperidinecarboxylate

Prepared from 1,1-dimethylethyl4-ethyl-4-hydroxy-1-piperidinecarboxylate (Description 51) according tothe method of Description 54. m/z (ES⁺) 244 (M+1).

DESCRIPTION 53 4-Ethyl-4-methoxypiperidine

Prepared from 1,1-dimethylethyl4-ethyl-4-methoxy-1-piperidinecarboxylate (Description 52) according tothe method of Description 75. m/z (ES⁺) 144 (M+1).

DESCRIPTION 54 Trans-(RS)-3-Methoxy-4-methyl-1-(phenylmethyl)piperidineHydrochloride

Sodium hydride (60% dispersion in mineral oil, 374 mg, 9.75 mmol) wasadded in portions to a solution oftrans-(RS)-4-methyl-1-phenylmethyl)-3-piperidinol (Tetrahedron 1970, 26,5519–5527, 1 g, 4.88 mmol) in dimethylformamide (30 mL) and the mixturewas stirred at room temperature for 1 hour. Iodomethane (304 μL, 4.88mmol) was added and the mixture was stirred at room temperature for 30minutes. The mixture was poured into water (300 mL) and extracted withdiethyl ether (2×200 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was suspended in diethyl ether (50 mL) and ethereal hydrogenchloride (1M, 5 mL) was added. The solid was collected and dried invacuo to give the title compound (720 mg, 60%). m/z (ES⁺) 220 (M+1).

DESCRIPTION 55 Trans-(RS)-3-Methoxy-4-methylpiperidine Hydrochloride

A slurry of palladium on carbon (10%, 100 mg) in ethanol (10 mL) wasadded to a solution oftrans-(RS)-3-methoxy-4-methyl-1-(phenylmethyl)piperidine hydrochloride(Description 54, 720 mg, 2.82 mmol) in ethanol (20 mL) and hydrochloricacid (2M, 10 mL) and the mixture was shaken under hydrogen (50 psi) for24 hours. The mixture was filtered through Celite™ and the solvent wasevaporated under reduced pressure to give the title compound as acolorless solid (488 mg, 99%). m/z (ES⁺) 130 (M+1).

DESCRIPTION 56 Trans-(RS)-4-Methyl-3-piperidinol Hydrochloride

A slurry of palladium on carbon (10%, 600 mg) in ethanol (10 mL) wasadded to a solution oftrans-(RS)-4-methyl-1-(phenylmethyl)-3-piperidinol (Tetrahedron 1970,26, 5519–5527, 6 g, 29.2 mmol) and hydrochloric acid (2M, 10 mL) inethanol (100 mL) and the mixture was shaken under hydrogen (50 psi) for42 hours. The mixture was filtered through Celite™ and the solvent wasevaporated under reduced pressure. Toluene (50 mL) was added andevaporated under reduced pressure to give the title compound as acolorless solid (4.4 g, 99%). m/z (ES⁺) 115 (M+1).

DESCRIPTION 57 Trans-(RS)-1,1-Dimethylethyl3-Hydroxy-4-methylpiperidinecarboxylate

Di-tert-butyl dicarbonate (4.32 g, 20 mmol) was added to a solution oftrans-(RS)-4-methyl-3-piperidinol hydrochloride (Description 56, 2.93 g,19.4 mmol) and triethylamine (4.1 mL, 29 mmol) in dichloromethane (150mL) and the mixture was stirred at room temperature for 16 hours.N,N-Dimethylethylenediamine (506 μL) was added and the mixture wasstirred at room temperature for 16 hours. The mixture was washed withaqueous citric acid (10%, 100 mL), dried (MgSO₄), and the solvent wasevaporated under reduced pressure to give the title compound as acolorless oil (4.0 g, 96%). m/z (ES⁺) 159 (M+1).

DESCRIPTION 58 Trans-(RS)-3-Fluoro-4-methylpiperidine Hydrochloride

Diethylaminosulphur trifluoride (880 μL, 6.66 mmol) was added to astirred, cooled (−40° C.) solution of trans-(RS)-1,1-dimethylethyl3-hydroxy-4-methylpiperidinecarboxylate (Description 57, 500 mg, 2.22mmol) in dichloromethane (50 mL). The mixture was allowed to warm toroom temperature and stirred for 16 hours. Ice (5 g) and water (5 mL)were added and the mixture was stirred for 20 minutes. The layers wereseparated and the aqueous layer was extracted with dichloromethane (2×50mL). The combined organic fractions were washed with brine (50 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was suspended in diethyl ether (50 mL) and treated withmethanolic hydrogen chloride (1M, 3 mL). The mixture was stirred at roomtemperature for 30 minutes, then the solvent was evaporated underreduced pressure to give the title compound as a solid (303 mg, 78%).m/z (ES⁺) 118 (M+1).

DESCRIPTION 59 (RS)-1,1-Dimethylethyl4-Methyl-3-oxopiperidinecarboxylate

1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (4.17 g,0.13 mmol) was added to a solution of trans-(RS)-1,1-dimethylethyl3-hydroxy-4-methylpiperidinecarboxylate (Description 57, 2 g, 9.3 mmol)in dichloromethane (60 mL) and the mixture was stirred at roomtemperature for 60 minutes. Aqueous sodium bisulfite (10%, 50 mL) wasadded and the mixture was stirred at room temperature for 5 minutes.Saturated aqueous sodium hydrogen carbonate (50 mL) was added and thelayers were separated. The organic fraction was dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give the title compound(1.96 g, 99%). m/z (ES⁺) 157 (M+1).

DESCRIPTION 60 (RS)-3,3-Difluoro-4-methylpiperidine Hydrochloride

Diethylaminosulphur trifluoride (1.18 mL, 8.97 mmol) was added to astirred, cooled (0° C.) solution of (RS)-1,1-dimethylethyl4-methyl-3-oxopiperidinecarboxylate (Description 59, 500 mg, 2.24 mmol)in dichloromethane and the mixture was stirred at room temperature for16 hours. Ice (5 g) and water (5 mL) were added and the mixture wasstirred at room temperature for 20 minutes. The layers were separatedand the aqueous layer was extracted with dichloromethane (2×50 mL). Thecombined organic fractions were washed with brine (50 mL), dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue wassuspended in diethyl ether (50 mL) and treated with methanolic hydrogenchloride (1M, 3 mL). The mixture was stirred at room temperature for 30minutes then the solvent was evaporated under reduced pressure to givethe title compound as a solid (303 mg, 78%). m/z (ES⁺) 136 (M+1).

DESCRIPTION 61(RS)-10-Methyl-7-(phenylmethyl)-1,4-dioxa-7-azaspiro[4.5]decaneHydrochloride

p-Toluenesulfonic acid (31 mg) was added to a solution of(RS)-4-methyl-1-phenylmethyl)-3-piperidinone (Tetrahedron 1970, 26,5519–5527, 1.55 g, 7.6 mmol) and ethylene glycol (20 mL, 0.35 mol) intoluene (76 mL) and the mixture was heated under reflux with azeotropicremoval of water overnight. The mixture was cooled, poured intosaturated aqueous potassium carbonate (150 mL) and extracted withdichloromethane (3×100 mL). The combined organic fractions were washedwith water, dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (96.5:3.5:1). The residuewas suspended in diethyl ether (50 mL) and ethereal hydrogen chloride(1M, 3 mL) was added. The solid was collected and dried in vacuo to givethe title compound (750 mg, 35%). m/z (ES⁺) 248 (M+1).

DESCRIPTION 62 (RS)-10-Methyl-1,4-dioxa-7-azaspiro[4.5]decaneHydrochloride

A slurry of palladium on carbon (10%, 90 mg) in ethanol (10 mL) wasadded to a solution of(RS)-10-methyl-7-phenylmethyl)-1,4-dioxa-7-azaspiro[4.5]decanehydrochloride (Description 61, 750 mg, 2.65 mmol) in ethanol (30 mL) andthe mixture was shaken under hydrogen (50 psi) for 24 hours. The mixturewas filtered through Celite™ and the solvent was evaporated underreduced pressure to give the title compound as a colorless solid (510mg, 99%). m/z (ES⁺) 158 (M+1).

DESCRIPTION 63 1,2,3,6-Tetrahydro-1-(phenylmethyl)-4-pyridineethanol

Benzyl bromide (4.4 mL, 41 mmol) was added to a solution of4-pyridineethanol (5 g, 41 mmol) in acetone (100 mL) and the mixture washeated under reflux for 16 hours. The mixture was cooled and the solidwas collected, washed with acetone (50 mL) and diethyl ether (2×50 mL)then dissolved in methanol (100 mL) and treated with sodium borohydride(6.2 g 164 mmol). The mixture was heated under reflux for 16 hours,cooled, and the solvent was evaporated under reduced pressure. Ethylacetate (200 mL) and aqueous sodium hydrogen carbonate (10%, 150 mL)were added and the layers were separated. The aqueous layer wasextracted with ethyl acetate (2×100 mL), the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (92:8:1), to give thetitle compound as a colorless oil (1.65 g, 18%). m/z (ES⁺) 218 (M+1).

DESCRIPTION 64 Trans-(RS)-3-Hydroxy-1-(phenylmethyl)-4-piperidineethanol

Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 16 mL) was addedto a solution of 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridineethanol(Description 63, 1 g, 4.6 mmol) in tetrahydrofuran (30 mL) and themixture was stirred at room temperature for 16 hours. Furtherborane-tetrahydrofuran complex (1M in tetrahydrofuran, 70 mL) was addedand the solution was heated under reflux for 72 hours. The mixture wascooled, a mixture of aqueous sodium hydroxide (4M, 200 mL) and aqueoushydrogen peroxide (37%, 200 mL) was added and the mixture was stirred atroom temperature for 2 hours. The mixture was extracted with ethylacetate (2×25 mL), the combined organic fractions were washed with brine(100 mL), dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH/Et₃N (95:5:1 increasing to90:10:1), to give the title compound (260 mg, 24%). m/z (ES⁺) 236 (M+1).

DESCRIPTION 65 Trans-(RS)-Octahydro-6-(phenylmethyl)furo[2,3-c]pyridine

Diethyl diazenedicarboxylate (191 μL, 1.2 mmol) was added to a solutionof trans-(RS)-3-hydroxy-1-phenylmethyl)-4-piperidineethanol (Description64, 260 mg, 1.1 mmol) and triphenylphosphine (328 mg, 1.2 mmol) intetrahydrofuran (60 mL) and the mixture was stirred at room temperaturefor 36 hours. The solvent was evaporated under reduced pressure,dichloromethane and water were added and the layers were separated. Theorganic layer was dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was dissolved in methanol (1.5 mL) andpoured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). Thecartridge was washed with methanol (4×2 mL), then eluted with methanolicammonia (2M, 2×2 mL). The solvent was evaporated under reduced pressureand the residue was purified by preparative thin layer chromatography onsilica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (96:4:1), to give thetitle compound (78 mg, 32%). m/z (ES⁺) 218 (M+1).

DESCRIPTION 66 Trans-(RS)-Octahydrofuro[2,3-c]pyridine Hydrochloride

A slurry of palladium on carbon (10%, 3 mg) in ethanol (10 mL) andconcentrated hydrochloric acid (1 mL) was added to a solution oftrans-(RS)-octahydro-6-(phenylmethyl)furo[2,3-c]pyridine (Description65, 78 mg) in ethanol (10 mL) and the mixture was shaken under hydrogen(50 psi) for 16 hours. The mixture was filtered through Celite™ and thesolvent was evaporated under reduced pressure. Toluene (2×5 mL) wasadded and evaporated under reduced pressure and the residue was dried invacuo to give the title compound (58 mg, 99%). m/z (ES⁺) 128 (M+1).

DESCRIPTION 67 1,1-Dimethylethyl4,4-Bis(hydroxymethyl)-1-piperidinecarboxylate

A solution of 1-(1,1-dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate(10 g, 39 mmol) in tetrahydrofuran (100 mL) was added to a stirred,cooled (−78° C.) solution of lithium diisopropylamide in tetrahydrofuran(0.82M, 140 mL) and the mixture was stirred at −78° C. for 2 h, then at−40° C. for 3 hours. The mixture was cooled to −78° C., ethylchloroformate (13 mL, 136 mmol) in tetrahydrofuran (80 mL) was added andthe mixture was allowed to warm to room temperature over 16 hours.Saturated aqueous ammonium chloride (50 mL), hydrochloric acid (1M, 2000mL) and ethyl acetate (3000 mL) were added and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×150mL), the combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was dissolved intoluene/tetrahydrofuran (1:1, 400 mL) and lithium borohydride (4.5 g,207 mmol) was added. The mixture was heated at 60° C. for 16 hours,cooled and saturated aqueous ammonium chloride was added slowly untilthe organic layer was a clear solution. The mixture was adjusted to pH12 with saturated aqueous sodium carbonate and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (2×150mL), the combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (50:50increasing to 0:100), to give the title compound (6.1 g, 63%). m/z (ES⁺)190 (M+1-C₄H₈).

DESCRIPTION 68 1,1-Dimethylethyl4-Hydroxymethyl-4-methanesulfonyloxymethyl-1-piperidinecarboxylate

Methanesulfonyl chloride (44 μL, 0.56 mmol) in dichloromethane (10 mL)was added slowly to a stirred, cooled (0° C.) solution of1,1-dimethylethyl 4,4-bis(hydroxymethyl)-1-piperidinecarboxylate(Description 67, 140 mg, 0.56 mmol) and triethylamine (95 μL, 0.68 mmol)in dichloromethane (50 mL). The mixture was allowed to warm to roomtemperature and stirred for 16 hours. Water (10 mL) was added and thelayers were separated. The aqueous layer was extracted withdichloromethane (2×40 mL), the combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (80:20 increasing to 0:100), to give thetitle compound (98 mg, 54%). m/z (ES⁺) 324 (M+1).

DESCRIPTION 69 1,1-Dimethylethyl2-Oxa-7-azaspiro[3.5]nonane-7-carboxylate

A solution of 1,1-dimethylethyl4-hydroxymethyl-4-methanesulfonyloxymethyl-1-piperidinecarboxylate(Description 68, 3 g, 9.3 mmol) in tetrahydrofuran (200 mL) was addeddropwise to a stirred suspension of sodium hydride (60% dispersion inmineral oil, 2.2 g, 55.8 mmol) in tetrahydrofuran (50 mL) and themixture was stirred at room temperature for 72 hours. Water (5 mL) wasadded and the mixture was extracted with ethyl acetate (3×400 mL). Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (80:20increasing to 50:50), to give the title compound (1.5 g, 71%). m/z (ES⁺)228 (M+1).

DESCRIPTION 70 2-Oxa-7-azaspiro[3.5]nonane

Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethyl2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (Description 69, 80 mg, 0.625mmol) in dichloromethane (15 mL) and the mixture was stirred at roomtemperature for 3 hours. Saturated aqueous sodium hydrogen carbonate (3mL) and dichloromethane (5 mL) were added and the layers were separated.The aqueous layer was extracted with dichloromethane (3×3 mL) and thecombined organic fractions were poured onto an SCX cartridge (VarianBond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent wasevaporated under reduced pressure to give the title compound as acolorless solid (8 mg, 17%). m/z (ES⁺) 128 (M+1).

DESCRIPTION 71 1,1-Dimethylethyl4-Hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate

Trimethyl(2-propynyloxy)silane (11.54 mL, 9.62 g, 75 mmol) was addeddropwise to a stirred, cooled (−5° C.) solution of ethyl magnesiumbromide (1M in tetrahydrofuran, 75 mL, 75 mmol) in tetrahydrofuran (150mL), maintaining the internal temperature below 0° C. The mixture wasstirred at 0° C. for 30 minutes, then at room temperature for 90minutes. The mixture was cooled to −5° C. and 1,1-methylethyl4-oxo-1-piperidinecarboxylate (15.0 g, 75 mmol) was added slowly,maintaining the internal temperature below 0° C. The mixture was stirredat 0° C. for 3 h then at room temperature for 96 hours. Saturatedaqueous ammonium chloride (300 mL), water (100 mL) and ethyl acetate(300 mL) were added and the layers were separated. The aqueous layer wasextracted with ethyl acetate (200 mL) and the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reduced pressureto give the title compound (24.4 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ4.36 (2H, s), 3.80–3.70 (2H, m), 3.35–3.25 (2H, m), 1.95–1.85 (2H, m),1.78–1.60 (3H, m), 1.48 (9H, s), and 0.2 (9H, s).

DESCRIPTION 72 1,1-Dimethylethyl4-Hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate

Tetrabutylammonium fluoride (1M in tetrahydrofuran, 80 mL, 80 mmol) wasadded to a solution of 1,1-dimethylethyl4-hydroxy-4-(3-trimethylsilyloxypropynyl)-1-piperidinecarboxylate(Description 71, 24.4 g, 75 mmol) in tetrahydrofuran (300 mL) and themixture was stirred at room temperature for 18 hours. The solvent wasevaporated under reduced pressure and water (200 mL) was added, Themixture was extracted with ethyl acetate (2×200 mL) and the combinedorganic fractions were washed with water (2×200 mL) and brine (200 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure togive the title compound as an orange oil (16.8 g, 88%). ¹H NMR (400 MHz,CDCl₃) δ 4.32 (2H, s), 3.80–3.68 (2H, m), 3.32–3.22 (2H, m), 1.93–1.83(2H, m), 1.75–1.65 (2H, m), 1.62 (1H, br s), and 1.46 (9H, s).

DESCRIPTION 73 1,1-Dimethylethyl4-Hydroxy-4-(3-proxypropyl)-1-piperidinecarboxylate

Palladium on carbon (5%, 800 mg) was added to a solution of1,1-dimethylethyl4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (Description 72,8.37 g, 32.8 mmol) in ethanol (400 mL), acetic acid (40 mL) and water (5mL) and the mixture was shaken under an atmosphere of hydrogen (40 psi)for 20 hours. The mixture was filtered through Hyflo™ and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (50:50increasing to 0:100), to give the title compound (4.84 g, 57%). ¹H NMR(400 MHz, CDCl₃) δ 3.85–3.75 (2H, m), 3.70 (2H, t, J 6 Hz), 3.18 (2H, brt, J 14 Hz), 2.00 (2H, br s), 1.73–1.65 (2H, m), 1.63–1.48 (6H, m), and1.46 (9H, s).

DESCRIPTION 74 1,1-Dimethylethyl1-Oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of diethyl diazenedicarboxylate (3.35 mL, 21.3 mmol) intetrahydrofuran (50 mL) was added over 15 minutes to a stirred, cooled(0° C.) solution of 1,1-dimethylethyl4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate (Description 73,4.6 g, 17.8 mmol) and triphenylphosphine (5.58 g, 21.3 mmol) intetrahydrofuran (150 mL) and the mixture was stirred at 0° C. for 1hour, then at room temperature for 24 hours. The solvent was evaporatedunder reduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with isohexane/EtOAc (75:25increasing to 50:50), to give the title compound (3.18 g, 70%). m/z(ES⁺) 242 (M+1).

DESCRIPTION 75 1-Oxa-8-azaspiro[4.5]decane Hydrochloride

Methanolic hydrogen chloride (3M, 20 mL) was added over 10 minutes to astirred, cooled (0° C.) solution of 1,1-dimethylethyl1-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 74, 3.18 g, 13.2mmol) in methanol (10 mL) and the mixture was stirred at roomtemperature for 3 hours. The solvent was evaporated under reducedpressure to give the title compound (2.29 g, 98%). m/z (ES⁺) 142 (M+1).

DESCRIPTION 76 1,1-Dimethylethyl4-(3-Ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate

n-Butyllithium (175 mL, 0.28 mol) was added dropwise over 45 minutes toa stirred, cooled (−70° C.) solution of ethyl propiolate (32 mL, 0.32mol) in tetrahydrofuran (250 mL). The mixture was stirred at −70° C. for10 minutes, then a solution of 1,1-dimethylethyl4-oxo-1-piperidinecarboxylate (18.6 g, 0.093 mol) in tetrahydrofuran(250 mL) was added dropwise over 1 hour maintaining the internaltemperature below −70° C. The mixture was stirred at −70° C. for 1 hour,acetic acid (21 mL) in tetrahydrofuran (50 mL) was added. The mixturewas warmed to room temperature and the solvent was evaporated underreduced pressure. Saturated aqueous sodium hydrogen carbonate (300 mL)and ethyl acetate (650 mL) were added and the layers were separated. Theaqueous fraction was extracted with ethyl acetate (2×650 mL) and thecombined organic fractions were washed with brine, dried (Na₂SO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by chromatography on a short silica gel column, eluting with1:1 isohexane:ethyl acetate, to give the title compound (29.2 g,contains trace impurity). m/z (ES⁺) 298 (M+1).

DESCRIPTION 77 1,1-Dimethylethyl4-(3-Ethoxy-3-oxoprop-1-yl)-4-hydroxy-1-piperidinecarboxylate

Palladium on carbon (5%, 1 g) in water (10 mL) was added to a solutionof 1,1-dimethylethyl4-(3-ethoxy-3-oxo-1-propynyl)-4-hydroxy-1-piperidinecarboxylate(Description 76, 14.6 g, 0.046 mol) in ethanol (200 mL) and the mixturewas shaken under hydrogen (45 psi) for 90 minutes. The mixture wasfiltered through a glass fibre pad and the solvent was evaporated underreduced pressure to give the title compound. m/z (ES⁺) 302 (M+1).

DESCRIPTION 78 1,1-Dimethylethyl1-Oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate

p-Toluenesulphonic acid (1.75 g, 9.2 mmol) was added to a solution of1,1-dimethylethyl4-(3-ethoxy-3-oxoprop-1-yl)-4-hydroxy-1-piperidinecarboxylate(Description 77, 27.63 g, 0.092 mol) in toluene (250 mL) and the mixturewas heated under reflux for 3 hours. The mixture was cooled and thesolvent was evaporated under reduced pressure. Water (400 mL) and ethylacetate (400 mL) were added and the layers were separated. The aqueousfraction was extracted with ethyl acetate (200 mL). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the title compound (20.86 g,88%). m/z (ES⁺) 256 (M+1).

DESCRIPTION 79 1-Oxa-8-azaspiro[4.5]decan-2-one Hydrochloride

Prepared from 1,1-dimethylethyl1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (Description 78)according to the method of Description 75. m/z (ES⁺) 156 (M+1).

DESCRIPTION 80 1,1-Dimethylethyl4-Hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate

1,1-Dimethylethyl 1-oxa-2-oxo-8-azaspiro[4.5]decane-8-carboxylate(Description 78, 5.0 g, 19.58 mmol) in tetrahydrofuran (150 mL) wasadded dropwise over 45 minutes to a stirred, cooled (0° C.) solution ofmethyl magnesium chloride (3M in tetrahydrofuran, 19.58 mL, 58.75 mmol)in tetrahydrofuran (150 mL). The mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was poured into saturatedaqueous ammonium chloride (200 mL) and extracted with ethyl acetate (200mL). The organic fraction was washed with brine, dried (Na₂SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting with ethylacetate, to give the title compound (3.9 g, 69%). m/z (ES⁺) 214(M+1-C₄H₈—H₂O).

DESCRIPTION 81 2,2-Dimethyl-1-oxa-8-azaspiro[4.5]decane

Trifluoroacetic acid (10 mL) was added to a solution of1,1-dimethylethyl4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate(Description 80, 3.9 g, 13.57 mmol) in dichloromethane (10 mL) and themixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(90:10:1) to give the title compound (2.04 g, 89%). m/z (ES⁺) 170 (M+1).

DESCRIPTION 82 1-(1,1-Dimethylethyl) 4-Ethyl4-(2-Propenyl)-1,4-piperidinedicarboxylate

A solution of 1-(1,1-Dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate(25.0 g, 97 mmol) in tetrahydrofuran (100 mL) was added slowly to astirred, cooled (−78° C.) solution of potassium hexamethyldisilazide(29.0 g, 145 mmol) in tetrahydrofuran (150 mL), maintaining the internaltemperature below −65° C. The mixture was stirred at −78° C. for 30minutes, then 3-bromopropene (12.6 mL, 145 mmol) was added dropwise over10 minutes. The mixture was stirred at −78° C. for 1 hour, thensaturated aqueous ammonium chloride (400 mL) and water (100 mL) wereadded and the mixture was warmed to room temperature. The mixture wasextracted with ethyl acetate (3×400 mL) and the combined organicfractions were washed with aqueous citric acid (10%, 2×250 mL),saturated aqueous sodium hydrogen carbonate (400 mL) and brine (200 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure togive the title compound (29.3 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ5.75–5.60 (1H, m), 5.10–5.00 (2H, m), 4.16 (2H, q, J 7 Hz), 3.92–3.78(2H, m), 2.90 (2H, br t, J 14 Hz), 2.26 (2H, d, J 7 Hz), 2.08 (2H, br d,J 14 Hz), 1.45 (9H, s), 1.45–1.30 (2H, m), and 1.26 (3H, t, J 7 Hz).

DESCRIPTION 83 1,1-Dimethylethyl1-Oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

1-(1,1-Dimethylethyl) 4-ethyl 4-(2-propenyl)-1,4-piperidinedicarboxylate(Description 82, 20.0 g, 67.2 mmol) was dissolved in methanol (300 mL)and dichloromethane (300 mL) and cooled to −78° C. Oxygen was bubbledthrough the solution for 10 minutes, then ozone for 75 minutes, to givea persistant blue coloration. Oxygen was bubbled through the solutionfor 10 minutes, then nitrogen for 10 minutes. Sodium borohydride (5.1 g,135 mmol) was added and the mixture was stirred at −78° C. for 1 hour.Further sodium borohydride (5.1 g, 135 mmol) was added and the mixturewas stirred at room temperature for 16 hours. Acetone (75 mL) was addedand the mixture was stirred at room temperature for 10 minutes. Water(50 mL) was added and the organic solvent was evaporated under reducedpressure. Saturated aqueous ammonium chloride (500 mL) was added and themixture was extracted with ethyl acetate (2×500 mL). The combinedorganic fractions were washed with aqueous citric acid (10%, 500 mL),saturated aqueous sodium hydrogen carbonate (500 mL) and brine (200 mL),dried (Na₂SO₄) and the solvent was evaporated under reduced pressure togive the title compound (15.0 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 4.31(2H, t, J 7 Hz), 3.97–3.87 (2H, m), 3.17–3.07 (2H, m), 2.20 (2H, t, J 7Hz), 1.92–1.82 (2H, m), 1.60–1.45 (2H, m), and 1.45 (9H, s).

DESCRIPTION 84 1,1-Dimethylethyl4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate

Diisobutylaluminium hydride (1.0M in dichloromethane, 3.60 mL, 3.60mmol) was added over 10 minutes to a stirred, cooled (−78° C.) solutionof 1,1-methylethyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(Description 83, 400 mg, 1.57 mmol) in dichloromethane (4 mL) and themixture stirred at −78° C. for 3 hours, then at 0° C. for 2 hours. Water(1.6 mL) was added very slowly at 0° C. and the mixture was warmed toroom temperature and stirred overnight. The mixture was filtered throughHyflo™, washing with dichloromethane, and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with ethyl acetate, to give thetitle compound (255 mg, 63%). m/z (ES⁺) 260 (M+1).

DESCRIPTION 85 1,1-Dimethylethyl2-Oxa-8-azaspiro[4.5]decane-8-carboxylate

Diethyl azodicarboxylate (183 μl, 1.16 mmol) in tetrahydrofuran (0.5 mL)was added dropwise to a stirred, cooled (0° C.) solution of1,1-demethylethyl4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate(Description 84, 250 mg, 0.96 mmol) and triphenylphosphine (303 mg, 1.16mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at 0° C.for 90 minutes then at room temperature overnight. The mixture wascooled to 0° C. and further triphenylphosphine (126 mg, 0.48 mmol) anddiethyl azodicarboxylate (76 μl, 0.48 mmol) were added. The mixture wasstirred at room temperature for 2.5 hours, then the solvent wasevaporated under reduced pressure and the residue was purified by flashcolumn chromatography on silica gel, eluting with 4:1 isohexane:ethylacetate, to give the title compound as a colorless oil (150 mg, 65%).m/z (ES⁺) 186 (M+1-C₄H₈).

DESCRIPTION 86 2-Oxa-8-azaspiro[4.5]decane

Methanolic hydrogen chloride (3M, 3 mL) was added to a stirred, cooled(0° C.) solution of 1,1-dimethylethyl2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 85, 150 mg, 0.62mmol) in methanol and the mixture was stirred at room temperature for 24hours. The solvent was evaporated under reduced pressure and the residuewas dissolved in methanol and passed through Amberlyst 26 ion exchangeresin, eluting with methanol. The solvent was evaporated under reducedpressure and the residue was dissolved in dichloromethane, dried(Na₂SO₄) and the solvent was evaporated under reduced pressure to givethe title compound (77 mg, 88%). m/z (ES⁺) 142 (M+1).

DESCRIPTION 87 1,1-Dimethylethyl4-(2-Hydroxyethyl)-4-(2-hydroxy-2-methylprop-1-yl)-1-piperidinecarboxylate

Prepared from 1,1-dimethylethyl1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 83)according to the method of Description 80. m/z (ES⁺) 288 (M+1).

DESCRIPTION 88 1,1-Dimethyl-2-oxa-8-azaspiro]4,5-decane

Prepared from 1,1-dimethylethyl4-(2-hydroxyethyl)-4-(2-hydroxy-2-methylprop-1-yl)-1-piperidinecarboxylate(Description 87) according to the method of Description 81. m/z (ES⁺)170 (M+1).

DESCRIPTION 89 1-(1,1-Dimethylethyl) 4-Ethyl4-(2-Methyl-2-propenyl)-1,4-piperidinedicarboxylate

A solution of 1-(1,1-dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate(12.85 g, 50 mmol) in tetrahydrofuran (50 mL) was added slowly to astirred, cooled (−78° C.) solution of potassium hexamethyldisilazide(14.96 g, 75 mmol) in tetrahydrofuran (75 mL), maintaining the internaltemperature below −65° C. The mixture was stirred at −78° C. for 30minutes, then 3-bromo-2-methylpropene (7.56 mL, 10.12 g, 75 mmol) wasadded dropwise over 5 minutes. The mixture was stirred at −78° C. for 1hour, then saturated aqueous ammonium chloride (200 mL) was added andthe mixture was warmed to room temperature. Water (100 mL) was added andthe mixture was extracted with ethyl acetate (3×200 mL). The combinedorganic fractions were washed with aqueous citric acid (10%, 3×200 mL),saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure togive the title compound as a pale yellow oil (15.48 g, 99%). m/z (ES⁺)256 (M+1-C₄H₈).

DESCRIPTION 90 1-(1,1-Dimethylethyl)4-(Hydroxymethyl)-4-(2-methyl-2-propenyl)-1-piperidinecarboxylate

Lithium borohydride (0.44 g, 20 mmol) was added to a solution of1-(1,1-dimethylethyl) 4-ethyl4-(2-methyl-2-propenyl)-1,4-piperidinedicarboxylate (Description 89,3.11 g, 10 mmol) in tetrahydrofuran and the mixture was stirred underreflux for 18 hours. The mixture was cooled, toluene (20 mL) and lithiumborohydride (0.44 g, 20 mmol) were added and the mixture was stirredunder reflux for 6 hours. The mixture was cooled and saturated aqueousammonium chloride (20 mL) and water (50 mL) were added. The mixture wasextracted with ethyl acetate (3×500 mL) and the combined organicfractions were washed with aqueous citric acid (10%, 50 mL), saturatedaqueous sodium hydrogen carbonate (50 mL) and brine (50 mL), dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (70:30) to give the title compound as acolorless foam (1.81 g, 67%). ¹H NMR (400 MHz, CDCl₃) shows two slowlyequilibrating tautomers; major: δ 4.92 (1H, s), 4.77 (1H, s), 3.86–3.20(10H, m), 2.14 (2H, s), 1.82 (3H, s), and 1.46 (9H, s); minor; δ 4.87(1H, s), 4.66 (1H, s), 3.86–3.20 (10H, m), 2.11 (2H, s), 1.76 (3H, s),and 1.46 (9H, s). m/z (ES⁺) 270 (M+1).

DESCRIPTION 91 3,3-Dimethyl-2-oxa-8-azaspiro[4.5]decane

Trifluoroacetic acid (20 mL) was added to a solution of1-(1,1-dimethylethyl)4-(hydroxymethyl)-4-(2-methyl-2-propenyl)-1-piperidinecarboxylate(Description 90, 1.14 g, 4.2 mmol) in dichloromethane (4 mL) and themixture was stirred at room temperature for 2 hours. The solvent wasevaporated under reduced pressure and water (40 mL) was added. The pHwas adjusted to 12 with aqueous sodium hydroxide (4M) and the mixturewas extracted with ethyl acetate (4×40 mL). The combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was dissolved in ethanol (10 mL) andethereal hydrogen chloride (1M, 10 mL) was added. The solvent wasevaporated under reduced pressure and the residue was triturated withethyl acetate (15 mL). The solid was collected and dried in vacuo togive the title compound as a colorless solid (483 mg, 56%). m/z (ES⁺)170 (M+1).

DESCRIPTION 92 3,3-Dimethyl-2-oxa-8-azaspiro[4.5]decan-1-one

Trifluoroacetic acid (50 mL) was added to a solution of1-(1,1-dimethylethyl) 4-ethyl4-(2-methyl-2-propenyl)-1,4-piperidinedicarboxylate (Description 89,10.86 g, 35 mmol) in dichloromethane (10 mL) and the mixture was stirredat 50 C for 8 hours. The mixture was cooled and the solvent wasevaporated under reduced pressure. Ether (50 mL) was added and themixture was extracted with hydrochloric acid (1M, 3×50 mL). The combinedaqueous fractions were washed with ether (2×50 mL), adjusted to pH 12with aqueous sodium hydroxide (4M) and the mixture was extracted withethyl acetate (6×50 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethanol (50 mL), cooled in ice and and etherealhydrogen chloride (1M, 35 mL) was added slowly. The solvent wasevaporated under reduced pressure, ethanol (75 mL) was added and themixture was heated under reflux for 15 minutes. The mixture was cooledand the solid was collected and dried in vacuo to give the titlecompound as a colorless solid (5.59 g, 73%), m.p.>280° C. m/z (ES⁺) 184(M+1).

DESCRIPTION 93 8-(Phenylmethyl)-2-oxa-8-azaspiro[4.5]decan-3-one

Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 60 mL, 60 mmol)was added to a suspension of α-ethyl4-carboxy-1-(phenylmethyl)-4-piperidineacetate hydrochloride (Helv.Chim. Acta 1972, 55, 2432–2438, 10.24 g, 30 mmol) in tetrahydrofuran(150 mL) and the mixture was stirred at room temperature for 3 days.Further borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 60 mL,60 mmol) was added and the mixture was stirred at room temperature for 1day. Methanol (20 mL) was added and the solvent was evaporated underreduced pressure. Methanol (200 mL) was added and the solvent wasevaporated under reduced pressure. Methanol (200 mL) was added and thesolvent was evaporated under reduced pressure. Hydrochloric acid (2M,200 mL) was added and the mixture was heated under reflux for 4 hours.The mixture was cooled. Ether (200 mL) was added and the layers wereseparated. The organic layer was extracted with hydrochloric acid (2M,2×100 mL) and the combined aqueous fractions were washed with ether(2×100 mL), adjusted to pH 10 with saturated aqueous potassium carbonateand extracted with dichloromethane (3×100 mL). The combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(aq.)(96:4:0.4), to give the title compound (3.4 g, 46%). m/z (ES⁺) 246(M+1).

DESCRIPTION 94 2-Oxa-8-azaspiro[4.5]decan-3-one Hydrochloride

Palladium on carbon (5%, 300 mg) was added to a solution of8-(phenylmethyl)-2-oxa-8-azaspiro[4.5]decan-3-one (Description 93, 2.80g, 11.4 mmol) in methanol/formic acid(10:1, 50 mL) and the mixture wasstirred at room temperature for 20 hours. Further palladium on carbon(5%, 300 mg) and formic acid (5 mL) were added and the mixture wasstirred at room temperature for 6 hours. Further palladium on carbon(5%, 300 mg) and formic acid (5 mL) were added and the mixture wasstirred at room temperature for 66 hours. The mixture was filtered andthe solvent was evaporated under reduced pressure. Portions ofhydrochloric acid (1M, 2×200 mL) then ethanol (3×100 mL) were added andevaporated under reduced pressure. The residue was triturated withethanol (50 mL) and refrigerated. The solid was collected and dried invacuo to give to give the title compound as a colorless solid (2.09 g,95%), m.p. 225–228° C. m/z (ES⁺) 156 (M+1).

DESCRIPTION 95 1,1-Dimethylethyl4-(Hydroxymethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate

Finely ground potassium hydroxide (248 mg, 44 mmol) was added to astirred, cooled (10° C.) solution of 1,1-dimethylethyl4,4-bis(hydroxymethyl)-1-piperidinecarboxylate (Description 67, 1.83 g,7.4 mmol), 18-crown-6 (196 mg, 0.74 mmol) and benzyl bromide (884 μL,7.4 mmol) in tetrahydrofuran (80 mL) and the mixture was stirred at roomtemperature for 16 hours. Brine (40 mL) was added and the layers wereseparated. The organic layer was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (80:20increasing to 50:50) to give the title compound (1.0 g, 40%). m/z (ES⁺)336 (M+1).

DESCRIPTION 96 1,1-Dimethylethyl4-Ethenyl-4-(phenylmethoxymethyl)-1-piperidinecarboxylate

1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.38 g, 3.3mmol) was added to a solution of 1,1-dimethylethyl4-(hydroxymethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate(Description 95, 1.06 g, 3 mmol) in dichloromethane (40 mL) and themixture was stirred at room temperature for 4 hours. Aqueous sodiumbisulfite (10%, 10 mL) was added and the mixture was stirred at roomtemperature for 5 minutes. Saturated aqueous sodium hydrogen carbonate(20 mL) was added and the layers were separated. The organic layer wasdried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (20 mL), and added to astirred, cooled (0° C.) solution of triphenylphosphoranylidine (0.1M, 50mL). The mixture was stirred at room temperature for 16 hours, then thesolvent was evaporated under reduced pressure. Ethyl acetate (40 mL) andaqueous sodium hydrogen carbonate (10%, 40 mL) were added and the layerswere separated. The organic layer was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc(75:25) give the title compound (1.01 g, 99%). m/z (ES⁺) 332 (M+1).

DESCRIPTION 97 (RS)-1,1-Dimethylethyl4-(1,2-Dihydroxyethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate

Osmium tetroxide (2.5 wt % solution in tert-butanol, 240 mL) was addedto a mixture of 1,1-dimethylethyl4-ethenyl-4-(phenylmethoxymethyl)-1-piperidinecarboxylate (Description96, 1.01 g, 3 mmol) and N-methylmorpholine-N-oxide (460 mg, 4 mmol) inwater (4 mL) and tetrahydrofuran (12 mL). The mixture was stirred atroom temperature for 24 hours then saturated aqueous sodium hydrogensulphate (5 mL) was added. The mixture was extracted with ethyl acetate(2×15 mL), the combined organic fractions were dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give the title compound(1.05 g, 96%). m/z (ES⁺) 366 (M+1).

DESCRIPTION 98 (RS)-1,1-Dimethylethyl4-Hydroxymethyl-4-(1,2-dihydroxyethyl)-1-piperidinecarboxylate

A slurry of palladium on carbon (10%, 100 mg) in ethanol (10 mL) wasadded to a solution of (RS)-1,1-dimethylethyl4-(1,2-dihydroxyethyl)-4-(phenylmethoxymethyl)-1-piperidinecarboxylate(Description 97, 1.05 g, 2.9 mmol) in ethanol (30 mL) and the mixturewas shaken under hydrogen (50 psi) for 72 hours. The mixture wasfiltered through Celite™ and the solvent was evaporated under reducedpressure to give the title compound as a pale oil (615 mg, 77%). m/z(ES⁺) 276 (M+1).

DESCRIPTION 99 (RS)-4-Hydroxy-2-oxa-8-azaspiro[4.5]decane Hydrochloride

Methanesulfonyl chloride (173 μL, 2.2 mmol) in dichloromethane (100 mL)was added dropwise to a solution of (RS)-1,1-dimethylethyl4-hydroxymethyl-4-(1,2-dihydroxyethyl)-1-piperidinecarboxylate(Description 98, 615 mg, 2.2 mmol) and triethylamine (933 μL, 6.6 mmol)in dichloromethane (150 mL) and the mixture was stirred at roomtemperature for 16 hours. Water (100 mL) was added and the layers wereseparated. The aqueous fraction was extracted with dichloromethane(2×100 mL), the combined organic fractions were dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting withisohexane/EtOAc (50:50) and the residue was suspended in diethyl ether(50 mL) and treated with methanolic hydrogen chloride (0.25M, 3 mL). Themixture was stirred at room temperature for 30 minutes, then the solventwas evaporated under reduced pressure to give the title compound as asolid (150 mg, 35%). m/z (ES⁺) 158 (M+1).

DESCRIPTION 100 (RS)-1-(1,1-Dimethylethyl) 4-Ethyl3-Oxo-1,4-piperidinedicarboxylate

Palladium hydroxide on carbon (20%, 2.9 g) and hydrochloric acid (2M, 50mL) were added to a solution of (RS)-ethyl3-oxo-1-(phenylmethyl)piperidinecarboxylate hydrochloride (25 g, 83.95mmol) in ethanol (320 mL) and the mixture was shaken under hydrogen (50psi) overnight. The mixture was filtered through a glass fibre pad andthe solvent was evaporated under reduced pressure. Dichloromethane (200mL), aqueous potassium carbonate (20%, 200 mL) and di-tert-butyldicarbonate (25.65 g, 117.53 mmol) were added and the mixture wasstirred at room temperature overnight. The layers were separated andN,N-dimethylethylenediamine (4.4 mL, 40 mmol) was added to the organicfraction. The mixture was stirred for at room temperature for 1 h,washed with aqueous citric acid (10%, 3×200 mL), water (2×200 mL) andbrine, dried (MgSO₄) and the solvent was evaporated under reducedpressure to give the title compound (21.8 g, 93%). m/z (ES⁺) 216(M+1-C₄H₈).

DESCRIPTION 101 (RS)-1-1,1-Dimethylethyl) 4-Ethyl3-Oxo-4-(2-propenyl)-1,4-piperidinedicarboxylate

Sodium hydride (60% dispersion in mineral oil, 1.47 g, 36.9 mmol) wasadded to a stirred, cooled (0° C.) solution of(RS)-1-(1,1-dimethylethyl) 4-ethyl 3-oxo-1,4-piperidinedicarboxylate(Description 100, 29 g, 107 mmol) in dimethylformamide (100 mL) and themixture was stirred at room temperature for 10 minutes. The mixture wascooled to (0° C.) and allyl bromide (4.68 mL, 55.3 mmol) was addedslowly. The mixture was warmed to room temperature and stirredovernight. Water (100 mL) was added and the mixture was extracted withethyl acetate (2×100 mL). The combined organic fractions were washedwith water (4×100 mL) and brine, dried (Na₂SO₄) and the solvent wasevaporated under reduced pressure to give the title compound (32.8 g,98%). m/z ES⁺ 256 (M+1-C₄H₈).

DESCRIPTION 102 Cis-(RS)- and Trans-(RS)-1-(1,1-Dimethylethyl) 4-Ethyl3-Hydroxy-4-(2-propenyl)-1,4-piperidinedicarboxylate

Sodium borohydride (4.05 g, 107 mmol) was added to a solution of(RS)-1-(1,1-dimethylethyl) 4-ethyl3-oxo-4-(2-propenyl)-1,4-piperidinedicarboxylate (Description 101, 32.8g, 105 mmol) in ethanol (300 mL) and the mixture was stirred at roomtemperature for 2 hours. Additional sodium borohydride (2 g, 53 mmol)was added and the mixture was stirred at room temperature overnight.Saturated aqueous ammonium chloride (100 mL) was added and the mixturewas basified with aqueous sodium carbonate (10%). The mixture wasextracted with ethyl acetate (2×350 mL) and the combined organicfractions were washed with brine, dried (Na₂SO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane:EtOAc(80:20), to give the title compound as a mixture of cis- andtrans-isomers (6.1 g, 18%). m/z ES⁺ 258 (M+1-C₄H₈).

DESCRIPTION 103 Cis-(RS)-1-(1,1-Dimethylethyl) 4-Ethyl3-(Phenylmethoxy)-4-(2-propenyl)-1,4-piperidinedicarboxylate andTrans-(RS)-1-(1,1-Dimethylethyl) 4-Ethyl3-(Phenylmethoxy)-4-(2-propenyl)-1,4-piperidinedicarboxylate

Sodium hydride (919 mg, 23 mmol) was added to a solution of cis-(RS)-and trans-(RS)-1-(1,1-dimethylethyl) 4-ethyl3-hydroxy-4-(2-propenyl)-1,4-piperidinedicarboxylate (Description 102,6.0 g, 19.1 mmol) in dimethylformamide (50 mL) and the mixture wasstirred at room temperature for 5 minutes. Benzyl bromide (2.73 mL, 23mmol) was added and the mixture was stirred at room temperatureovernight. Water (50 mL) was added and the mixture was extracted withethyl acetate (2×50 mL). The combined organic fractions were washed withwater (3×50 mL) and brine, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with 9:1 isohexane:ethyl acetate.The residue was purified by MPLC on silica gel, eluting withisohexane/ethyl acetate (90:10), to givetrans-(RS)-1-(1,1-dimethylethyl) 4-ethyl3-(phenylmethoxy)-4-(2-propenyl)-1,4-piperidinedicarboxylate; ¹H NMR(400 MHz, DMSO-d₆) δ 7.38–7.24 (5H, m), 5.67–5.56 (1H, m), 5.00 (1H, d,J 1.8, Hz), 4.97 (1H, d, J 8.8 Hz), 4.72–4.68 (1H, m), 4.40 (1H, d, J11.4 Hz), 4.23 (1H, d, J 14.0 Hz), 4.12 (2H, q, J 7 Hz), 3.84 (1H, d, J13.1 Hz), 3.75 (1H, d, J 2.5 Hz), 2.86 (1, d, J 14.4 Hz), 2.74 (1H, m),2.46–2.41 (1H, m), 2.26–2.21 (1H, m), 1.80 (1H, d, J 13.4 Hz), 1.59 (1H,dt, J 4.5, 12.8 Hz), 1.35 (9H, s), and 1.19 (3H, t, J 7 Hz); m/z (ES⁺)404 (M+1); and cis-(RS)-1-(1,1-dimethylethyl) 4-ethyl3-(phenylmethoxy)-4-(2-propenyl)-1,4-piperidinedicarboxylate; ¹H NMR(400 MHz, DMSO-d₆) δ 7.33–7.21 (5H, m), 5.64–5.53 (1H, m), 5.11–4.98(2H, m), 4.63–4.58 (1H, m), 4.32 (1H, d, J 11.3 Hz), 4.18 (1H, d, J 14.0Hz), 4.09–395 (2H, m), 3.84 (1H, d, J 13.4 Hz), 3.58 (1H, s), 3.05 (1H,d, J 14.5 Hz), 2.91 (1H, m), 2.56–2.49 (1H, m), 2.35–2.29 (1H, m), 1.93(1H, dt, J 4.8, 13.5 Hz), 1.47 (1H, d, J 14.1 Hz), 1.34 (9H, s), and1.12 (3H, t, J 7 Hz); m/z (ES⁺) 348 (M+1-C₄H₈).

DESCRIPTION 104 Trans-(RS)-1,1-Dimethylethyl6-(Phenylmethoxy)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Prepared from trans-(RS)-1-(1,1-dimethylethyl) 4-ethyl3-phenylmethoxy)-4-(2-propenyl)-1,4-piperidinedicarboxylate (Description103) according to the method of Description 124. m/z (ES⁺) 362 (M+1).

DESCRIPTION 105 Trans-(RS)-1,1-Dimethylethyl6-Hydroxy-1-oxo-2-oxa-8-azaspiro[4,5]-decane-8-carboxylate

Prepared from trans-(RS)-1,1-dimethylethyl6-(phenylmethoxy)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(Description 104) according to the method of Description 98. m/z (ES⁺)272 (M+1)

DESCRIPTION 106

Trans-(RS)-6-Hydroxy-2-oxa-8-azaspiro[4.5]decan-1-one Hydrochloride

Prepared from trans-(RS)-1,1-dimethylethyl6-hydroxy-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description105) according to the method of Description 75. m/z (ES⁺) 172 (M+1).

DESCRIPTION 107 Cis-(RS)-1,1-Dimethylethyl6-(Phenylmethoxy)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Prepared from cis-(RS)-1-(1,1-dimethylethyl) 4-ethyl3-(phenylmethoxy)-4-(2-propenyl)-1,4-piperidinedicarboxylate(Description 103) according to the method of Description 124. m/z (ES⁺)328 (M+1-C₄H₈).

DESCRIPTION 108 Cis-(RS)-1,1-Dimethylethyl6-Hydroxy-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Prepared from cis-(RS)-1,1-dimethylethyl6-(phenylmethoxy)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(Description 107) according to the method of Description 98. ¹H NMR (400MHz, DMSO-d₆) δ 5.41 (1H, d, J 4.5 Hz), 4.25–4.15 (2H, m), 3.78 (1H, dd,J 12, 5 Hz), 3.65 (1H, br d, J 13 Hz), 3.50–3.42 (1H, m), 3.28–3.05 (2H,m), 2.45–2.35 (1H, m), 2.00 (1H, dt, J 13, 8 Hz), 1.85 (1H, dt, J 14, 3Hz), 1.50 (1H, dt, J 14, 5 Hz), and 1.40 (9H, s).

DESCRIPTION 109 Cis-(RS)-6-Hydroxy-2-oxa-8-azaspiro[4.5]decan-1-oneHydrochloride

Prepared from cis-(RS)-1,1-dimethylethyl6-hydroxy-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description108) according to the method of Description 75. m/z (ES⁺) 172 (M+1).

DESCRIPTION 110 Trans-(RS)-1,1-Dimethylethyl4-(2-Hydroxyethyl)-4-(hydroxymethyl)-3-(phenylmethoxy)-1-piperidinecarboxylate

Prepared from trans-(RS)-1,1-dimethylethyl6-(phenylmethoxy)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(Description 104) according to the method of Description 114. m/z (ES⁺)366 (M+1).

DESCRIPTION 111 Trans-(RS)-1,1-Dimethylethyl6-(Phenylmethoxy)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Prepared from trans-(RS)-1,1-dimethylethyl4-(2-hydroxyethyl)-4-(hydroxymethyl)-3-(phenylmethoxy)-1-piperidinecarboxylate(Description 110) according to the method of Description 115. m/z (ES⁺)292 (M+1-C₄H₈).

DESCRIPTION 112 Trans-(RS)-1,1-Dimethylethyl6-Hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Prepared from trans-(RS)-1,1-dimethylethyl6-(phenylmethoxy)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description111) according to the method of Description 116. m/z (ES⁺) 202(M+1-C₄H₈).

DESCRIPTION 113 Trans-(RS)-2-Oxa-8-azaspiro[4.5]decan-6-ol Hydrochloride

Prepared from trans-(RS)-1,1-dimethylethyl6-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 112)according to the method of Description 75. m/z (ES⁺) 158 (M+1).

DESCRIPTION 114 Cis-(RS)-1,1-Dimethylethyl4-(2-Hydroxyethyl)-4-(hydroxymethyl)-3-(phenylmethoxy)-1-piperidinecarboxylate

Lithium borohydride (523 mg, 24.0 mmol) was added to a solution ofcis-(RS)-1,1-dimethylethyl6-(phenylmethoxy)-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate(Description 107, 2.9 g, 8.0 mmol) in tetrahydrofuran/toluene (3:1, 40mL) and the mixture was stirred at 50° C. overnight. Further lithiumborohydride (261 mg, 12 mmol) was added and the mixture was stirred at50° C. for 5 hours. The mixture was cooled, acidified with hydrochloricacid (1M) and extracted with ethyl acetate (2×100 mL). The combinedorganic fractions were washed with brine, dried (Na₂SO₄) and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with 1:3 isohexane:ethylacetate, to give the title compound (2.5 g, 85%). m/z (ES⁺) 310(M+1-C₄H₈).

DESCRIPTION 115 Cis-(RS)-1,1-Dimethylethyl6-(Phenylmethoxy)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

A solution of methanesulphonyl chloride (514 μl, 6.62 mmol) indichloromethane (150 mL) was added over 30 minutes to a solution ofcis-(RS)-1,1-dimethylethyl4-(2-hydroxyethyl)-4-(hydroxymethyl)-3-(phenylmethoxy)-1-piperidinecarboxylate(Description 114, 2.42 g, 6.62 mmol) and pyridine (1.61 mL, 19.86 mmol)in dichloromethane (150 mL) and the mixture was stirred at roomtemperature overnight. Further batches of of methanesulphonyl chloride(514 μl, 6.62 mmol) and pyridine (1.61 mL, 19.86 mmol) were added attwo-hourly intervals until all the starting material was consumed byTLC. The mixture was washed with aqueous citric acid (10%, 300 mL),aqueous sodium hydroxide (1M, 300 mL) and brine, dried (Na₂SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting with 4:1isohexane:ethyl acetate, to give the title compound (1.47 g, 64%). m/z(ES⁺) 191 (M+1-C₄H₈).

DESCRIPTION 11 Cis-(RS)-1,1-Dimethylethyl6-Hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

Palladium on carbon (5%, 500 mg) was added to a solution ofcis-(RS)-1,1-dimethylethyl6-(phenylmethoxy)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description115, 1.47 g, 4.23 mmol) and acetic acid (2.5 mL) in methanol (50 mL) andthe mixture was shaken under hydrogen (50 psi) overnight. The mixturewas filtered through a glass fibre pad and the solvent was evaporatedunder reduced pressure to give the title compound (1.03 g, 95%). m/z(ES⁺) 202 (M+1-C₄H₈).

DESCRIPTION 117 Cis-(RS)-2-Oxa-8-azaspiro[4.5]decan-6-ol Hydrochloride

Prepared from cis-(RS)-1,1-dimethylethyl6-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 116)according to the method of Description 75. m/z (ES⁺) 158 (M+1).

DESCRIPTION 118 Trans-(RS)-1,1-Dimethylethyl6-Fluoro-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(Diethylamino)sulphur trifluoride (772 μl, 5.9 mmol) was added slowly toa stirred, cooled (−40° C.) solution of cis-(RS)-1,1-dimethylethyl6-hydroxy-1-oxo-2-oxa-8-azaspiro[4,5]decane-8-carboxylate (Description108, 200 mg, 0.74 mmol) in dichloromethane (20 mL) and the mixture wasstirred at −40° C. for 3 h and at room temperature overnight. Water (50mL) and dichloromethane (30 mL) were added and the layers wereseparated. The organic fraction was washed with brine, dried (Na₂SO₄)and the solvent was evaporated under reduced pressure to give crudetitle compound (225 mg,). m/z (ES⁺) 218 (M+1-C₄H₈).

DESCRIPTION 119 Trans-(RS)-6-Fluoro-2-oxa-8-azaspiro[4.5]decan-1-oneHydrochloride

Prepared from trans-(RS)-1,1-dimethylethyl6-fluoro-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description118) according to the method of Description 75. m/z (ESP) 174 (M+1).

DESCRIPTION 120 Trans-(RS)-1,1-Dimethylethyl2-Oxa-6-oxo-8-azaspiro[4.5]decane-8-carboxylate

1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (758 mg,1.79 mmol) was added to a solution of trans-(RS)-1,1-dimethylethyl6-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 112,230 mg, 0.89 mmol) in dichloromethane (10 mL) and the mixture wasstirred at room temperature for 1 hour. Aqueous sodium bisufite (10%, 15mL) and saturated aqueous sodium hydrogen carbonate (15 mL) were addedand the mixture was stirred at room temperature for 20 minutes. Themixture was extracted with dichloromethane (2×15 mL) and the combinedorganic fractions were washed with brine, dried (Na₂SO₄) and the solventwas evaporated under reduced pressure to give the title compound (230mg, 100%). m/z (ES⁺) 200 (M+1-C₄H₈).

DESCRIPTION 121 Trans-(RS)-1,1-Dimethylethyl6,6-Difluoro-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

(Diethylamino)sulphur trifluoride (436 μl, 3.56 mmol) was added to astirred, cooled (−40° C.) solution of trans-(RS)-1,1-dimethylethyl2-oxa-4-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 120, 230mg, 0.89 mol) in dichloromethane (10 mL) and the mixture was stirred at−40° C. for 2 h then at room temperature for 2 hours. Water (20 mL) wasadded carefully and the mixture was extracted with dichloromethane (2×20mL). The combined organic fractions were washed with brine, dried(Na₂SO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with 4:1 isohexane:ethyl acetate, to give the title compound (46mg, 19%). ¹H NMR (400 MHz, CDCl₃) δ 3.99 (1H, d, J 10 Hz), 3.93–3.83(2H, m), 3.75–3.64 (1H, m), 3.59 (1H, d, J 10 Hz), 3.58–3.50 (2H, m),3.4–3.3 (1H, m), 2.23–2.15 (1H, m), 1.8–1.65 (2H, m), and 1.47 (10H, s).

DESCRIPTION 122 (RS)-6,6-Difluoro-2-oxa-8-azaspiro[4.5]decane

Prepared from trans-(RS)-1,1-dimethylethyl6,6-difluoro-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 121)according to the method of Description 193. m/z (ES⁺) 178 (M+1).

DESCRIPTION 123 (RS)-1-(1,1-Dimethylethyl) 3-Ethyl3-(2-Propenyl)-1,3-piperidinedicarboxylate

1-(1,1-Dimethylethyl) 3-ethyl 1,3-piperidinedicarboxylate (12.85 g, 50mmol) in tetrahydrofuran (50 mL) was added slowly to a stirred, cooled(−78° C.) solution of potassium hexamethyldisilazide (14.96 g, 75 mmol)in tetrahydrofuran (75 mL). The mixture was stirred at −78° C. for 30minutes, then 3-bromo-1-propene (6.49 mL, 9.07 g, 75 mmol) was addeddropwise over 5 minutes. The mixture was stirred at −78° C. for 1 hour,then saturated aqueous ammonium chloride (200 mL) and water (100 mL)were added. The mixture was allowed to warm to room temperature andextracted with ethyl acetate (3×200 mL). The combined organic fractionswere washed with aqueous citric acid (10%, 3×200 mL), saturated aqueoussodium hydrogen carbonate (200 mL) and brine (200 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give to give thetitle compound as a pale yellow oil (13.46 g, 91%). m/z (ES⁺) 298 (M+1).

DESCRIPTION 124 (RS)-1,1-Dimethylethyl2-Oxa-1-oxo-7-azaspiro[4.5]decan-7-carboxylate

(RS)-1-(1,1-Dimethylethyl) 3-ethyl3-(2-propenyl)-1,3-piperidinedicarboxylate (Description 123, 13.46 g, 45mmol) was dissolved in methanol (200 mL) and dichloromethane (320 mL)and cooled to −78° C. Oxygen was bubbled through the solution for 10minutes, then ozone for 75 minutes, to give a persistan blue coloration.Oxygen was bubbled through the solution for 10 minutes, then nitrogenfor 10 minutes. Sodium borohydride (3.43 g, 90 mmol) was added and themixture was stirred at −78° C. for 1 hour. Further sodium borohydride(3.43 g, 90 mmol) was added and the mixture was stirred at 0–5° C. for 1hour. Acetone (50 mL) was added and the mixture was stirred at roomtemperature for 1 hour. Saturated aqueous ammonium chloride (200 mL) wasadded and the organic solvent was evaporated under reduced pressure.Water (100 mL) was added and the mixture was extracted with ethylacetate (3×200 mL). The combined organic fractions were washed withaqueous citric acid (10%, 200 mL), saturated aqueous sodium hydrogencarbonate (200 mL) and brine (200 mL), dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was recrystallised fromhexane/EtOAc (96:4, 50 mL) and the solid was collected and dried invacuo to give the title compound as a colorless solid (9.20 g, 80%). m/z(ES⁺) 199 (M+1-C₄H₈).

DESCRIPTION 125 (RS)-2-Oxa-7-azaspiro[4.5]decan-1-one Hydrochloride

Trifluoroacetic acid (50 mL) was added to a solution of(RS)-1,1-dimethylethyl 2-oxa-1-oxo-7-azaspiro[4.5]decan-7-carboxylate(Description 124, 7.67 g, 30 mmol) in dichloromethane (10 mL) and themixture was stirred at room temperature for 4 hours. The solvent wasevaporated under reduced pressure, ether (40 mL) was added and themixture was extracted with hydrochloric acid (1M, 3×40 mL). The combinedaqueous fractions were washed with ether (2×40 mL), adjusted to pH 12.0with saturated aqueous potassium carbonate and extracted withdichloromethane (10×50 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethanol (30 mL) and ethereal hydrogen chloride(1M, 30 mL) was added. The mixture was refrigerated and the solid wascollected and dried in vacuo. The residue was suspended in propan-2-ol(50 mL) and the mixture was heated under reflux for 15 minutes. Themixture was cooled and the solid was collected and dried in vacuo at 40°C. to give the title compound as a cream solid (3.09 g, 54%), m.p.197–200° C. m/z (ES⁺) 156 (M+1).

DESCRIPTION 126 (RS)-1,1-Dimethylethyl3-(2-Hydroxyethyl)-3-(hydroxymethyl)-1-piperidinecarboxylate

Prepared from (RS)-1,1-dimethylethyl2-oxa-1-oxo-7-azaspiro[4.5]decane-7-carboxylate (Description 124)according to the method of Description 84. m/z (ES⁺) 160 (M+1).

DESCRIPTION 127 (RS)-1,1-Dimethylethyl2-Oxa-7-azaspiro[4.5]decane-7-carboxylate

Methanesulfonyl chloride (0.295 mL, 382 mmol) was added to a stirred,cooled (0° C.) solution of (RS)-1,1-dimethylethyl3-(2-hydroxyethyl)-3-hydroxymethyl)-1-piperidinecarboxylate (Description126, 989 mg, 3.82 mmol) and pyridine (0.925 mL, 11.4 mmol) indichloromethane (10 mL) and the mixture was stirred at room temperaturefor 2 hours. Aqueous citric acid (10%, 50 mL) was added and the mixturewas extracted with dichloromethane (3×30 mL). The combined organicfractions were dried (Na₂SO₄), the solvent was evaporated under reducedpressure and the residue was purified by flash column chromatography onsilica gel, eluting with isohexane/EtOAc (90:10), to give the titlecompound (315 mg, 34%). ¹H NMR (360 MHz, CDCl₃) δ 3.85–3.70 (2H, m),3.60 (1H, d, J 10 Hz), 3.55–3.35 (3H, m), 3.31–3.23 (1H, m), 3.18 (1H,d, J 14 Hz), 1.85–1.75 (1H, m), 1.65–1.50 (5H, m), and 1.45 (9H, s).

DESCRIPTION 128 (RS)-2-Oxa-7-azaspiro[4.5]decane Hydrochloride

Prepared from (RS)-1,1-dimethylethyl2-oxa-7-azaspiro[4.5]decane-7-carboxylate (Description 127) according tothe method of Description 75. m/z (ES⁺) 142 (M+1).

DESCRIPTION 129 1,1-Dimethylethyl4-Hydroxy-4-(2-propenyl)-1-piperidinecarboxylate

Prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate accordingto the method of Description 51, substituting allyl magnesium chloridefor ethyl magnesium bromide. m/z (ES⁺) 186 (M+1-C₄H₈).

DESCRIPTION 130 1,1-Dimethylethyl4-(2-Propenyl)-4-(2-propenyloxy)-1-piperidinecarboxylate

Sodium hydride (60% dispersion in mineral oil, 12 g, 0.3 mol) was addedslowly to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl4-hydroxy-4-(2-propenyl)-1-piperidinecarboxylate (Description 129, 23.1g, 0.096 mol) in dimethylformamide (200 mL) and the mixture was stirredat 0° C. for 10 minutes. Allyl bromide (25.4 ml, 0.3 mol) was added andthe mixture was stirred at 0° C. for 5 minutes, then at room temperaturefor 45 minutes. The mixture was cooled to 0° C. and water (200 mL) wasadded. The mixture was extracted with diethyl ether (2×200 mL) and thecombined organic fractions were washed with water (4×200 mL) and brine(150 mL), dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with isohexane/EtOAc (9:1), to give the titlecompound (5.5 g, 20%). m/z (E) 226 (M+1-C₄H₈).

DESCRIPTION 131 1,1-Dimethylethyl1-Oxa-9-azaspiro[5.5]undec-3-en-9-carboxylate

Solutions of 1,1-dimethylethyl4-(2-propenyl)-4-(2-propenyloxy)-1-piperidinecarboxylate (Description130, 4.9 g, 17.4 mmol) in dichloromethane (1.2 L) andbis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (717mg, 0.87 mmol) in dichloromethane (1.2 L) were added dropwisesimultaneously to dichloromethane (600 mL) over a period of 8 hours, andthe mixture was stirred at room temperature overnight. The solvent wasevaporated under reduced pressure and the residue was purified by flashcolumn chromatography on silica gel, eluting with 9:1 isohexane:ethylacetate, to give the title compound (3.3 g, 75%). m/z (ES⁺) 254 (M+1).

DESCRIPTION 132 1-Oxa-9-azaspiro[5.5]undec-3-ene

Prepared from 1,1-dimethylethyl1-oxa-9-azaspiro[5.5]undec-3-en-9-carboxylate (Description 131)according to the method of Description 193. m/z (ES⁺) 154 (M+1).

DESCRIPTION 133 (RS)-1,1-Dimethylethyl3-Hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate and(RS)-1,1-Dimethylethyl4-Hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate

Borane tetrahydrofuran complex (1M in tetrahydrofuran, 23.68 mL, 23.68mmol) was added dropwise to a solution of 1,1-dimethylethyl1-oxa-9-azaspiro[5.5]undec-3-en-9-carboxylate (Description 131, 2.0 g,7.89 mmol) in tetrahydrofuran (30 mL) and the mixture was stirred atroom temperature for 6.5 hours. Water (25 mL), aqueous sodium hydroxide(4M, 25 mL) and hydrogen peroxide (37%, 25 mL) were added and themixture was stirred at room temperature for 20 minutes. Water (100 mL)and diethyl ether (100 mL) were added and the layers were separated. Theaqueous fraction was extracted with diethyl ether (100 mL) and thecombined organic fractions were washed with brine, dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting with ethylacetate. The residue was purified by MPLC on silica gel, eluting withethyl acetate, to give 1,1-dimethylethyl3-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (520 mg, 24%); ¹HNMR (360 MHz, CDCl₃) δ 3.76–3.71 (4H, m), 3.50–3.45 (1H, m), 3.16–3.07(2H, m), 1.92–1.85 (3H, m), 1.75–1.63 (2H, m), 1.46 (9H, s), and1.45–1.35 (3H, m); and 1,1-dimethylethyl4-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (200 mg, 9%);. ¹HNMR (400 MHz, CDCl₃) δ 4.02–3.93 (1H, m), 3.87–3.83 (1H, m), 3.75–3.71(2H, m), 3.57 (1H, dt, J 2.3, 11.7 Hz), 3.19 (1H, t, J 11.3 Hz), 3.03(1H, t, J 11.7 Hz), 1.95–1.87 (2H, m), 1.86–1.81 (1H, m), 1.68–1.65 (1H,m), 1.57–1.47 (2H, m), 1.45 (9H, s), and 1.41–1.28 (2H, m).

DESCRIPTION 134 (RS)-1-Oxa-9-azaspiro[5.5]undecan-3-ol

Prepared from of 1,1-dimethylethyl3-hydroxy-1-oxa-9-azaspiro[5.5]undecane-9-carboxylate (Description 133)according to the method of Description 193. m/z (ES⁺) 172 (M+1).

DESCRIPTION 135 1-(1,1-Dimethylethyl) 4-Phenylmethyl4-(3-Butenyl)-1,4-piperidinedicarboxylate

Lithium hexamethyldisilazide (1M in tetrahydrofuran, 15.7 mL, 15.7 mmol)was added dropwise to a stirred, cooled (−78° C.) solution of1-(1,1-dimethylethyl) 4-phenylmethyl 1,4-piperidinedicarboxylate (2.50g, 7.83 mmol) in tetrahydrofuran (50 mL) and the mixture was stirred at−78° C. for 2 hours. 4-Bromo-1-butene (1.99 mL, 19.6 mmol) was addeddropwise and the mixture was stirred at −78° C. for 1 hour, then at roomtemperature for 2 hours. Water (100 mL) was added and the mixture wasextracted with ethyl acetate (2×100 mL). The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with isohexane/EtOAc (90:10) to give the titlecompound (1.07 g, 37%). ¹H NMR (400 MHz CDCl₃) δ 7.4–7.3 (5H, m),5.75–5.6 (1H, m), 5.15 (2H, s), 4.93 (1H, br d, J 7 Hz), 4.90 (1H, brs), 3.95–3.75 (2H, m), 2.93–2.78 (2H, m), 2.13 (2H, br d, J 10 Hz),1.95–1.85 (2H, m), 1.65–1.55 (2H, m), 1.44 (9H, s), and 1.43–1.30 (2H,m).

DESCRIPTION 136 1-(1,1-Dimethylethyl) 4-Phenylmethyl4-(3-Hydroxypropyl)-1,4-piperidinedicarboxylate

A solution of 1-(1,1-dimethylethyl) 4-phenylmethyl4-(3-butenyl)-1,4-piperidinedicarboxylate (Description 135, 1.06 g, 2.84mmol) in dichloromethane/methanol (50:50, 20 mL) was cooled to −78° C.and oxygen was bubbled through the mixture for 10 minutes. Ozone wasbubbled through the mixture until a blue coloration persisted. Oxygenwas bubbled through the mixture for 10 minutes, then nitrogen for 10minutes. Sodium borohydride (1.1 g, 28.9 mmol) was added over 5 minutesand the mixture was allowed to warm to room temperature. The solvent wasevaporated under reduced pressure and water (40 mL) was added. Themixture was extracted with ethyl acetate (3×40 mL), the combined organicfractions were dried (Na₂SO₄) and the solvent was evaporated underreduced pressure to give the title compound (1.06 g, 99%). ¹H NMR (400MHz, CDCl₃) δ 7.4–7.3 (5H, m), 5.15 (2H, s), 3.95–3.75 (2H, m), 3.52(2H, t, J 7 Hz), 2.95–2.80 (2H, m), 2.12 (2H, br d, J 10 Hz), 1.65–1.30(7H, m), and 1.44 (9H, s).

DESCRIPTION 137 1,1-Dimethylethyl4-(Hydroxymethyl)-4-(3-hydroxypropyl)-1-piperidinecarboxylate

Lithium borohydride (500 mg, 22.7 mmol) was added to a solution of1-(1,1-dimethylethyl) 4-phenylmethyl4-(3-hydroxypropyl)-1,4-piperidinedicarboxylate (Description 136, 1.05g, 2.79 mmol) in tetrahydrofuran/toluene (50:50, 20 mL). and the mixturewas stirred at 60° C. for 4 hours. The mixture was cooled andhydrochloric acid (2M, 10 mL) was added. The mixture was poured intoaqueous sodium carbonate (10%, 100 mL) and extracted with ethyl acetate(3×50 mL). The combined organic fractions were dried (Na₂SO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting with EtOAc/MeOH(100:0 increasing to 95:5) to give the title compound (563 mg, 74%). ¹HNMR (400 MHz, CDCl₃) δ 3.67 (2H, t, J 7 Hz), 3.48 (2H, s), 3.47–3.40(2H, m), 3.35–3.25 (2H, m), 1.7 (2H, br s), 1.6–1.3 (8H, m), and 1.44(9H, s).

DESCRIPTION 138 1,1-Dimethylethyl2-Oxa-9-azaspiro[5.5]undecane-9-carboxylate

Diethyl diazenedicarboxylate (390 μL, 2.46 mmol) was added to a solutionof 1,1-dimethylethyl4-(hydroxymethyl)-4-(3-hydroxypropyl)-1-piperidinecarboxylate(Description 137, 560 mg, 2.05 mmol) and triphenylphosphine (646 mg,2.46 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred atroom temperature for 24 hours. Further triphenylphosphine (646 mg, 2.46mmol) and diethyl diazenedicarboxylate (390 μL, 2.46 mmol) were addedand the mixture was stirred at room temperature for 24 hours. Methanol(5 mL) was added and the solvent was evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (75:25), to give the title compound (78 mg,15%). m/z (ES⁺) 256 (M+1).

DESCRIPTION 139 2-Oxa-9-azaspiro[5.5]undecane

Acetyl chloride (1 mL) was added to stirred, cooled (0° C.) methanol (10mL) and the mixture was stirred at 0° C. for 5 minutes.1,1-Dimethylethyl 2-oxa-9-azaspiro[5.5]undecane-9-carboxylate(Description 138, 78 mg, 0.27 mmol) was added and the mixture wasstirred at room temperature for 3 hours. The solvent was evaporatedunder reduced pressure, aqueous sodium carbonate (10%, 10 mL) was addedand the mixture was extracted with dichloromethane (3×10 mL). Thecombined organic fractions were dried (Na₂SO₄) and the solvent wasevaporated under reduced pressure to give the title compound (50 mg,100%). m/z (ES⁺) 156 (M+1).

DESCRIPTION 140 Phenylmethyl4-[(1-Methyl-1H-1,2,4-triazol-5-yl)methyl]-3-oxo-1-piperazinecarboxylate

Sodium hydride (60% dispersion in mineral oil, 281 mg, 7.0 mmol) wasadded to a solution of phenylmethyl 3-oxo-1-piperazinecarboxylate (1.5g, 6.4 mmol) in dry dimethyl formamide (5 mL) and the mixture wasstirred at room temperature for 30 minutes.5-(Chloromethyl)-1-methyl-1H-1,2,4-triazole (WO0023449, 920 mg, 7.0mmol) was added and the mixture was stirred at room temperature for 16hours. The mixture was poured into water (150 mL) and extracted withdiethyl ether (2×100 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure to givethe title compound as a pale oil (2 g, 94%). m/z (ES⁺) 330 (M+1).

DESCRIPTION 1411-[(1-Methyl-1H-1,2,4-triazol-5-yl)methyl]-2-oxopiperazine

A slurry of palladium on carbon (10%, 1.7 g) and 1,4-cyclohexadiene (4.1g, 51 mmol) in ethanol (10 mL) was added to a solution of phenylmethyl4-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-3-oxo-1-piperazinecarboxylate(Description 140, 1.7 g, 5.2 mmol) in ethanol (40 mL) and the mixturewas stirred at room temperature for 2 hours. The mixture was filteredthrough Celite™ and the solvent was evaporated under reduced pressure,The residue was recrystallized from propan-2-ol to give the titlecompound (500 mg, 49%). m/z (ES⁺) 196 (M+1).

DESCRIPTION 142 2-[(2-Hydroxyethyl)amino]-N-(3-pyridinyl)acetamide

Chloroacetyl chloride (2.2 mL, 27.6 mmol) was added dropwise over 10minutes to a stirred, cooled (0° C.) solution of 3-pyridinamine (2 g, 21mmol) and triethylamine (4 mL, 28 mmol) in tetrahydrofuran (30 mL). Themixture was allowed to warm to room temperature, then 2-aminoethanol (5mL, 120 mmol) in methanol (5 mL) was added. The mixture was stirred at60° C. for 4 hours, cooled and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (90:10:1), to give thetitle compound (2.53 g, 62%). m/z (ES⁺) 196 (M+1).

DESCRIPTION 143 1-(3-Pyridinyl)piperazin-2-one

Bis(1,1-dimethylethyl)diazenedicarboxylate (4.1 g, 18 mmol) intetrahydrofuran (100 mL) was added dropwise to a stirred, cooled (0° C.)solution of 2-[(2-hydroxyethyl)amino]-N-(3-pyridinyl)acetamide(Description 142, 2.5 g, 13 mmol) and tributylphosphine (4.2 mL, 16.9mmol) in tetrahydrofuran (300 mL) and the mixture was stirred at roomtemperature for 16 hours. Ethereal hydrogen chloride (1M, 10 mL) wasadded and the mixture was stirred at room temperature for 1 hour.Triethylamine (6 mL, 42 mmol) was added the solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(90:10:1), to give the title compound (800 mg, 35%). m/z (ES⁺) 178(M+1).

DESCRIPTION 144 2-[(2-Hydroxyethyl)amino]-N-(2-thiazolyl)acetamide

Prepared from 2-thiazolamine according to the method of Description 142.m/z (ES⁺) 202 (M+1).

DESCRIPTION 145 1-(2-Thiazolyl)piperazin-2-one

Prepared from 2-[(2-hydroxyethyl)amino]-N-(2-thiazolyl)acetamide(Description 144) according to the method of Description 143. m/z (ES⁺)184 (M+1).

DESCRIPTION 146 N-Phenylmethyl-N′-(2-pyridinyl)-1,2-ethanediamine

2-Bromopyridine (6.1 mL, 64 mmol) was added toN-(phenylmethyl)-1,2-ethanediamine (50 ml, 322 mmol) and the mixture washeated at 130–140° C. for 2 hours. The mixture was cooled, diluted withethyl acetate (500 mL), washed with water (3×150 mL), dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (90:8:1), to give the title compound as a yellowoil (5.7 g, 40%). m/z (ES⁺) 228 (M+1).

DESCRIPTION 147 N-Phenylmethyl-N′-(4-pyridinyl)-1,2-ethanediamine

Prepared from 4-bromopyridine according to the method of Description146. m/z (ES⁺) 228 (M+1).

DESCRIPTION 148N-Phenylmethyl-N′-(6-chloro-2-pyridinyl)-1,2-ethanediamine

Prepared from 2,6-dichloropyridine according to the method ofDescription 146. m/z (ES⁺) 262, 264 (M+1).

DESCRIPTION 149 N-(Phenylmethylaminoethyl)-2-pyrazinamine

Prepared from 2-bromopyrazine according to the method of Description146. m/z (ES⁺) 229 (M+1).

DESCRIPTION 150 4-Phenylmethyl-1-(2-pyridinyl)piperazin-2-one

Glyoxal trimeric dihydrate (15.8 g, 75 mmol) was added to a mixture ofN-phenylmethyl-N′-(2-pyridinyl)-1,2-ethanediamine (Description 146, 5.7g, 25 mmol) and hydrochloric acid (2N, 100 mL) and the mixture wasstirred at room temperature for 24 hours. Further glyoxal trimericdihydrate (5.3 g, 25 mmol) was added and the mixture was stirred at roomtemperature for 20 hours. The mixture was basified with aqueous sodiumhydroxide (4M) and extracted with ethyl acetate (2×200 mL). The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with isohexane/EtOAc (40:60increasing to 30:70), to give the title compound as a light brown oil(3.6 g, 54%). m/z (ES⁺) 268 (M+1).

DESCRIPTION 151 4-Phenylmethyl-1-(4-pyridinyl)piperazin-2-one

Prepared from N-phenylmethyl-N′-4-pyridinyl)-1,2-ethanediamine(Description 147) according to the method of Description 150. m/z (ES⁺)268 (M+1).

DESCRIPTION 152 4-Phenylmethyl-1-(6-chloro-2-pyridinyl)piperazin-2-one

Prepared from N-phenylmethyl-N′-(6-chloro-2-pyridinyl)-1,2-ethanediamine(Description 148) according to the method of Description 150. m/z (ES⁺)302, 304 (M+1).

DESCRIPTION 153 4-Phenylmethyl-1-pyrazinylpiperazinone

Prepared from N-(phenylmethylaminoethyl)-2-pyrazinamine (Description149) according to the method of Description 150. ¹H NMR (400 MHz, CDCl₃)δ 9.41 (1H, d, J 1.5 Hz), 8.36 (1H, dd, J 2.5, 1.5 Hz), 8.33 (1H, d, J2.5 Hz), 7.40–7.25 (5H, m), 3.98 (2H, t, J 5.5 Hz), 3.65 (2H, s), 3.40(2H, s), and 2.85 (2H, t, J 5.5 Hz).

DESCRIPTION 154 1-(2-Pyridyl)piperazin-2-one

A slurry of palladium on carbon (5%, 3.6 g) in water was added to asolution of 4-phenylmethyl-1-(2-pyridinyl)piperazin-2-one (Description150, 3.6 g, 13.48 mmol) and ammonium formate (4.25 g, 67.5 mmol) inmethanol (100 mL) and the mixture was heated under reflux for 4 hours,cooled and filtered through Hyflo™, washing with methanol. The solventwas evaporated under reduced pressure and the residue was purified byflash column chromatography on silica gel eluting with CH₂Cl₂/MeOH(90:10), to give the title compound as an orange oil (1.1 g, 46%). m/z(ES⁺) 178 (M+1).

DESCRIPTION 155 1-(4-Pyridinyl)piperazin-2-one

Prepared from 4-phenylmethyl-1-(4-pyridinyl)piperazin-2-one (Description151) according to the method of Description 154. m/z (ES⁺) 178 (M+1).

DESCRIPTION 156 1-Pyrazinylpiperazin-2-one

Prepared from 4-phenylmethyl-1-pyrazinylpiperazinone (Description 153)according to the method of Description 154. m/z (ES⁺) 179 (M+1).

DESCRIPTION 157 1-(6-chloro-2-pyridinyl)piperazin-2-one

1-Chloroethylchloroformate (143 μL, 1.33 mmol) was added slowly to astirred, cooled (−18° C.) solution of4-phenylmethyl-1-(6-chloro-2-pyridinyl)piperazin-2-one (Description 152,400 mg, 1.33 mmol) in dichloromethane (10 mL) and the mixture wasstirred at −14° C. for 3 hours. The solvent was evaporated under reducedpressure, methanol (10 mL) was added and the mixture was heated underreflux for 30 minutes. The mixture was cooled, the solvent wasevaporated under reduced pressure and methanolic ammonia (2M, 10 mL) wasadded. The solvent was evaporated under reduced pressure and the residuewas purified by flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (120:8:1), to give the title compound as a tan gum(118 mg, 42%). m/z (ES⁺) 212, 214 (M+1)⁺.

DESCRIPTION 158N-[(1,1-Dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine MethylEster

Di-tert-butyl dicarbonate (6.0 g, 28 mmol) was added to a solution ofN-(1,1-dimethylethyl)glycine methyl ester (J. Org. Chem 1995, 60, 5814,4.0 g, 28 mmol) in dichloromethane (20 mL) and the mixture was stirredat room temperature for 16 hours. Further di-tert-butyl dicarbonate (3.0g, 14 mmol) was added and mixture was stirred at room temperature for 72hours. N,N-dimethylethylenediamine (3.2 mL, 28 mmol) was added and themixture was stirred at room temperature for 1 hour. The mixture waswashed with aqueous citric acid (10%, 2×40 mL), saturated aqueous sodiumhydrogen carbonate (30 mL) and brine (30 mL), dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give the title compoundas a yellow oil (5.6 g, 82%). ¹H NMR (400 MHz, CDCl₃) δ 1.40 (9H, s),1.45 (9H, s), 3.72 (3H, s), and 4.05 (2H, s).

DESCRIPTION 159N-[(1,1-Dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine

Aqueous sodium hydroxide (4M, 5 mL) was added to a solution ofN-[(1,1-dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine methylester (Description 158, 2.0 g, 8.2 mmol) in methanol (10 mL) and themixture was stirred at room temperature for 40 hours. The solvent wasevaporated under reduced pressure, hydrochloric acid (2M, 20 mL) wasadded and the mixture was extracted with dichloromethane (3×40 mL). Thecombined organic fractions were washed with brine, dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give the title compoundas a colorless oil (1.6 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 1.41 (9H, s),1.46 (9H, s), and 4.08 (2H, s).

DESCRIPTION 160 1,1-DimethylethylN-(1,1-Dimethylethyl)-N-(2-oxoethyl)carbamate

Diisobutylaluminium hydride (1M in toluene, 3.7 mL, 3.7 mmol) was addedto a stirred, cooled (−78° C.) solution ofN-[(1,1-dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine methylester (Description 158, 900 mg, 3.7 mmol) in toluene (5 mL) and themixture was stirred at −78° C. for 3 hours. Hydrochloric acid (1M, 5 mL)was added and the mixture was allowed to warm to room temperature. Themixture was extracted with ethyl acetate (2×40 mL) and the combinedorganic fractions were washed with brine, dried (MgSO₄) and the solventwas evaporated under reduced pressure to give the title compound as acolorless oil (688 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 1.39 (9H, s),1.45 (9H, s), 4.01 (2H, s), and 9.54 (1H, s).

DESCRIPTION 161N-(2-Chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-Imidazole-2-methanamine

A mixture of 2-chloroethylamine hydrochloride (8.23 g, 71 mmol),triethylamine (15.8 mL, 0.11 mol) and1-(2-trimethylsilyl)ethoxymethyl-2-imidazolecarboxaldehyde (12.9 g, 57mmol) in 1,2-dichloroethane (400 mL) was heated under reflux until allthe solids dissolved. The mixture was cooled and sodiumtriacetoxyborohydride (15.0 g, 71 mmol) was then added in portions over15 minutes. The mixture was stirred at room temperature for 3 h, thenpoured into aqueous sodium hydroxide (1M, 250 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×200mL). The combined organic fractions were washed with brine (150 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with CH₂Cl₂/MeOH (95:5), to give the title compound as acolorless oil (5.0 g, 30%). m/z (ES⁺) 290 (M+1).

DESCRIPTION 162 1,1-DimethylethylN-(2-Chloroethyl)-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-ylmethyl)carbamate

Di-tert-butyl dicarbonate (4.14 g, 19 mmol) was added in portions over 2minutes to a stirred, cooled (0° C.) solution ofN-(2-chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-methanamine(Description 161, 5.0 g, 17.3 mmol) in dichloromethane (200 mL) and themixture was at 0° C. for 10 minutes, then at room temperature for 1hour. The solvent was evaporated under reduced pressure and the residuewas purified by flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH (98:2), to give the title compound (2.52 g, 34%). m/z (ES⁺)390 (M+1).

DESCRIPTION 163 1,1-Dimethylethyl5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazin-7-carboxylate

Tetrabutylammonium fluoride (1M in tetrahydrofuran, 7.1 mL, 7.1 mmol)was added to a solution of 1,1-dimethylethylN-(2-chloroethyl)-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-ylmethyl)carbamate(Description 162, 2.52 g, 6.5 mmol) in tetrahydrofuran (50 mL) and themixture was heated under reflux for 1.5 hours. Furthertetrabutylammonium fluoride (1M in tetrahydrofuran, 7.1 mL, 7.1 mmol)was added and the mixture was heated under reflux for 20 hours. Themixture was cooled and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH (97:3), to give the title compound(505 mg, 35%). m/z (ES⁺) 224 (M+1).

DESCRIPTION 164 5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazineTrifluoroacetate

1,1-Dimethylethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-carboxylate(Description 163, 505 mg, 2.26 mmol) in dichloromethane (2.5 mL) wasadded to stirred, cooled (0° C.) trifluoroacetic acid (5 mL) and themixture was stirred at 0° C. for 15 minutes, then at room temperaturefor 45 minutes. The solvent was evaporated under reduced pressure togive the title compound. m/z (ES⁺) 124 (M+1).

DESCRIPTION 1651-{[(2-Trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-methanol and1-{[(2-Trimethylsilyl)ethoxy]methyl}-1H-imidazole-5-methanol

1H-Imidazole-4-methanol hydrochloride (5.0 g, 37.2 mmol) indimethylformamide (100 mL) was added dropwise over 30 minutes to asuspension of sodium hydride (60% dispersion in mineral oil, 2.97 g,74.3 mmol) in dimethylformamide (200 mL) and the mixture was stirred atroom temperature for 2 hours. The mixture was cooled to 0° C. and asolution of [2-(chloromethoxy)ethyl]trimethysilane (6.59 mL, 37.2 mmol)in tetrahydrofuran (50 mL) was added dropwise over 15 minutes. Themixture was stirred at room temperature overnight, then water (100 mL)was added and the solvent was evaporated under reduced pressure. Toluene(200 mL) was added and evaporated under reduced pressure. Water (100 mL)was added and the mixture was extracted with ethyl acetate (3×150 mL).The combined organic fractions were washed with water (100 mL) and brine(150 mL), dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH (95:5 increasing to 90:10), to givethe title compound as a mixture of isomers (4.82 g, 57%). ¹H NMR (400MHz, CDCl₃) δ Major isomer, δ 0.00 (9H, s), 0.84–0.96 (2H, m), 3.43–3.56(2H, m), 4.62 (2H, s), 5.24 (2H, s), 6.99 (1H, s), and 7.56 (1H, s);Minor isomer, δ 0.00 (9H, s), 0.84–0.96 (2H, m), 3.43–3.56 (2H, m), 4.67(2H, s), 5.36 (2H, s), 7.05 (1H, s), and 7.56 (1H, s). m/z (ES⁺) 229(M+1).

DESCRIPTION 1661-(2-Trimethylsilyl)ethoxymethyl-4-imidazolecarboxaldehyde and1-(2-Trimethylsilyl)ethoxymethyl-5-imidazolecarboxaldehyde

Manganese (IV) oxide (18.4 g, 0.21 mol) was added in portions over 5minutes to a solution of1-{[(2-trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-methanol and1-{[(2-trimethylsilyl)ethoxy]methyl}-1H-imidazole-5-methanol (Mixture ofisomers, Description 165, 4.82 g, 21.1 mmol) in dichloromethane (500 mL)and the mixture was stirred at room temperature overnight. The mixturewas filtered through Celite™, washing with dichloromethane (200 mL), andthe solvent was evaporated under reduced pressure to give the titlecompound as a mixture of isomers (4.78 g, 99%). ¹H NMR (400 MHz, CDCl₃)δ Major isomer, 0.00 (9H, s), 0.87–0.93 (2H, m), 3.56–3.65 (2H, m), 5.72(2H, s), 7.84 (1H, s), 7.89 (1H, s), and 9.81 (1H, s); Minor isomer,0.02 (9H, s), 0.87–0.97 (2H, m), 3.47–3.58 (4H, m), 5.35 (2H, s), 7.70(1H, s), 7.75 (1H, s), 9.93 (1H, s).

DESCRIPTION 167N-(2-Chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-4-methanamineandN-(2-Chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-5-methanamine

Prepared from 1-(2-trimethylsilyl)ethoxymethyl-4-imidazolecarboxaldehydeand 1-(2-trimethylsilyl)ethoxymethyl-5-imidazolecarboxaldehyde (Mixtureof isomers, Description 166) according to the method of Description 161,followed by purification by flash column chromatography on silica gel,eluting with CH₂Cl₂/MeOH (95:5 increasing to 85:15), to giveN-(2-chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-4-methanamine(1.97 g, 45%); ¹H NMR (400 MHz, CDCl₃) δ 0.00 (9H, s), 0.92 (2H, t, J8.3 Hz), 2.95 (2H, t, J 5.7 Hz), 3.44–3.53 (2H, m), 3.60–3.68 (2H, m),3.88 (2H, s), 5.39 (2H, s), 6.99 (1H, s), and 7.61 (1H, s); m/z (ES⁺)290 (M+1); andN-(2-chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-5-methanamine(1.02 g, 23%); ¹H NMR (400 MHz, CDCl₃) δ 0.00 (9H, s), 0.92 (2H, t, J8.1 Hz), 3.08 (2H, t), J 6.0 Hz), 3.44–3.53 (2H, m), 3.73 (2H, t, J 6.0Hz), 3.88 (2H, s), 5.24 (2H, s), 7.06 (1H, s), and 7.60 (1H, s); m/z(ES⁺) 290 (M+1).

DESCRIPTION 168 1,1-DimethylethylN-(2-Chloroethyl)-N-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-ylmethyl)carbamate

Prepared fromN-(2-chloroethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1-imidazole-4-methanamine(Description 167) according to the method of Description 162. m/z (ES⁺)390 (M+1).

DESCRIPTION 169 1,1-Dimethylethyl5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazin-7-carboxylate

Prepared from 1,1-dimethylethyl N-(2-chloroethyl)-N1-{[2-trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-ylmethyl)carbamate(Description 168) according to the method of Description 163. ¹H NMR(360 MHz, CDCl₃) δ 1.49 (9H, s), 3.80 (2H, t, J 5.5 Hz), 4.03 (2H, t, J5.5 Hz), 4.65 (2H, s), 6.85 (1H, s), and 7.44 (1H, s).

DESCRIPTION 170 5,6,7,8-Tetrahydroimidazo[1,5-a]pyrazineTrifluoroacetate

Prepared from 1,1-dimethylethyl5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-7-carboxylate (Description 169)according to the method of Description 164. m/z (ES⁺) 124 (M+1).

DESCRIPTION 171 Methyl 2-Fluorobenzeneacetate

Prepared from 2-fluorobenzeneacetic acid according to the method ofDescription 1. ¹H NMR (400 MHz, CDCl₃) δ 7.28–7.24 (2H, m), 7.13–7.04(2H, m), 3.71 (3H, s), and 3.68 (2H, s).

DESCRIPTION 172 Methyl 3-Fluorobenzeneacetate

Prepared from 3-fluorobenzeneacetic acid according to the method ofDescription 1. ¹H NMR (400 MHz, CDCl₃) δ 7.31–7.26 (1H, m), 7.06–6.95(3H, m), 3.71 (3H, s), and 3.62 (2H, s).

DESCRIPTION 173 Methyl 4-Fluorobenzeneacetate

Prepared from 4-fluorobenzeneacetic acid according to the method ofDescription 1. ¹H NMR (360 MHz, CDCl₃) δ 7.25–7.22 (2H, m), 7.03–6.99(2H, m), 3.70 (3H, s), and 3.60 (2H, s).

DESCRIPTION 174 Dimethyl1-(2-Fluorophenyl)-4-oxo-1,3-cyclohexanedicarboxylate

Prepared from methyl 2-fluorobenzeneacetate (Description 171) accordingto the method of Description 16. ¹H NMR (400 MHz, CDCl₃) δ 12.12 (1H,s), 7.29–7.24 (1H, m), 7.22–7.17 (1H, m), 7.12–7.00 (2H, m), 3.83 (3H,s), 3.69 (3H, s), 2.37–2.32 (3H, m), 2.28–2.27 (1H, m), and 1.96–1.82(2H, m).

DESCRIPTION 175 Dimethyl1-(3-Fluorophenyl)-4-oxo-1,3-cyclohexanedicarboxylate

Prepared from methyl 3-fluorobenzeneacetate (Description 172) accordingto the method of Description 16. ¹H NMR (360 MHz, CDCl₃) δ 12.11 (1H,s), 7.33–7.26 (1H, m), 7.13 (1H, m), 7.06 (1H, dt, J 2.2, 10.6 Hz),6.99–6.95 (1H, m), 3.83 (3H, s), 3.65 (3H, s), 3.07 (1H, dd, J 1.4, 16.1Hz), 2.71 (1H, d, J 16.1 Hz), 2.47–2.38 (2H, m), and 2.22–2.16 (2H, m).

DESCRIPTION 176 Dimethyl1-(4-Fluorophenyl)-4-oxo-1,3-cyclohexanedicarboxylate

Prepared from methyl 4-fluorobenzeneacetate (Description 173) accordingto the method of Description 16. ¹H NMR (400 MHz, CDCl₃) δ 12.10 (1H,s), 7.34–7.31 (2H, m), 7.04–7.00 (2H, m), 3.81 (3H, s), 3.64 (3H, s),3.06 (1H, dd, J 1.2, 16.1 Hz), 2.71 (1H, d, J 16.1 Hz), 2.44–2.37 (2H,m), and 2.21–2.14 (2H, m).

DESCRIPTION 177 1-(2-Fluorophenyl)-4-oxocyclohexanecarboxylic Acid

Prepared from dimethyl1-(2-fluorophenyl)-4-oxo-1,3-cyclohexanedicarboxylate (Description 174)according to the method of Description 17. ¹H NMR (360 MHz, CDCl₃) δ741–7.29 (2H, m), 7.2–16.97 (21 m), 2.78–2.65 (3H, m), and 2.46–2.21(5H, m).

DESCRIPTION 178 1-(3-Fluorophenyl)-4-oxocyclohexanecarboxylic Acid

Prepared from dimethyl1-(3-fluorophenyl)-4-oxo-1,3-cyclohexanedicarboxylate (Description 175)according to the method of Description 17. ¹H NMR (360 MHz, CDCl₃) δ7.39–7.35 (1H, m), 7.31–7.25 (1H, m), 7.21–7.18 (1H, m), 7.05–7.00 (1H,m), 2.78–2.73 (2H, m), 2.63–2.55 (2H, m), 2.47–2.41 (2H, m), and2.30–2.23 (2H, m).

DESCRIPTION 179 1-(4-Fluorophenyl)-4-oxocyclohexanecarboxylic Acid

Prepared from dimethyl1-(4-fluorophenyl)-4-oxo-1,3-cyclohexanedicarboxylate (Description 176)according to the method of Description 17. ¹H NMR (360 MHz, CDCl₃) δ7.48–7.46 (2H, m), 7.11–7.02 (2H, m), 2.79–2.73 (2H, m), 2.62–2.53 (2H,m), 2.46–2.34 (2H, m), and 2.30–2.22 (2H, m).

DESCRIPTION 180 1-(2-Fluorophenyl)-4-oxocyclohexylamine Hydrochloride

Prepared from 1-(2-fluorophenyl)-4-oxocyclohexanecarboxylic Acid(Description 177) according to the method of Description 18. ¹H NMR (400MHz, DMSO-d₆) δ 8.93 (3H, br s), 7.70–7.65 (1H, m), 7.55–7.51 (1H, m),7.41–7.37 (2H, m), 2.75–2.61 (4H, m), 2.45–2.37 (2H, m), and 2.33–2.29(2H, m).

DESCRIPTION 181 1-(3-Fluorophenyl)-4-oxocyclohexylamine Hydrochloride

Prepared from 1-(3-fluorophenyl)-4-oxocyclohexanecarboxylic Acid(Description 178) according to the method of Description 18. ¹H NMR (400MHz, DMSO-d₆) δ 8.94 (3H, br s), 7.62–7.54 (3H, m), 7.31–7.24 (1H, m),2.69–2.59 (4H, m), 2.42–2.34 (2H, m), and 2.28–2.20 (2H, m).

DESCRIPTION 182 1-(4-Fluorophenyl)-4-oxocyclohexylamine Hydrochloride

Prepared from 1-(4-fluorophenyl)-4-oxocyclohexanecarboxylic Acid(Description 179) according to the method of Description 18. ¹H NMR (400MHz, DMSO-d₆) δ 8.88 (3H, br s), 7.81–7.76 (2H, m), 7.36–7.28 (2H, m),2.70–2.55 (4H, m), 2.43–2.36 (2H, m), and 2.25–2.18 (2H, m).

DESCRIPTION 183 4-Oxo-1-(2-pyridyl)cyclohexanecarboxylic AcidHydrochloride

Ethyl 2-pyridineacetate (30.0 g, 27.7 mL, 182 mmol) was added over 30minutes to a stirred, cooled (0° C.) suspension of sodium hydride (60%dispersion in mineral oil, 23.2 g, 581 mmol) in dimethylformamide (400mL) (internal temperature<2° C.) and the mixture was stirred at 0° C.for 30 minutes. Methyl 2-propenoate (37.6 mL, 418 mmol) was addeddropwise over 2 hours (internal temperature<10° C.) and the mixture wasstirred at room temperature for 24 hours. The mixture was cooled to 0°C. and the pH was adjusted to 3.0 with hydrochloric acid (2M, 300 mL).The mixture was extracted with ethyl acetate (2×400 mL) and the combinedorganic fractions were washed with brine (200 mL), dried (Na₂SO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withisohexane/EtOAc (75:25), to give a solid (18.7 g). A portion (9.27 g)was suspended in hydrochloric acid (5M, 250 mL) and heated under refluxfor 20 hours. The mixture was cooled, the solvent was evaporated underreduced pressure and the residue was dried in vacuo to give the titlecompound (7.62 g, 32%). ¹H NMR (400 MHz, CD₃OD) δ 9.24 (1H, m), 8.57(1H, t, J 7 Hz), 8.15 (1H, d, J 7 Hz), 8.10 (1H, t, J 7 Hz), 2.55–2.40(4H, m), 2.25–2.10 (2H, m), and 1.95–1.80 (2H, m)

DESCRIPTION 184 4-Oxo-1-(2-pyridyl)cyclohexanecarboxyl Azide

Oxalyl chloride (3.41 mL, 39.7 mmol) was added to a mixture of4-oxo-1-(2-pyridyl)cyclohexanecarboxylic acid hydrochloride (Description183, 2.03 g, 7.94 mmol) and dimethylformamide (2 drops) indichloromethane (20 mL). The mixture was heated under reflux for 2.5hours, cooled and the solvent was evaporated under reduced pressure.Dichloromethane (2×10 mL) was added and evaporated under reducedpressure. The residue was suspended in dichloromethane (20 mL) and asolution of sodium azide (1.55 g, 23.8 mmol) and tetrabutylammoniumbromide (250 mg, 0.77 mmol) in water (15 mL) was added. The mixture wasstirred at room temperature for 18 hours, then aqueous potassiumcarbonate (10%, 100 mL) was added. The mixture was extracted withdichloromethane (2×50 mL), the combined organic fractions were washedwith water (2×50 mL), dried (Na₂SO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane/EtOAc (66:33increasing to 50:50), to give the title compound as a colorless oil(0.57 g, 29%). ¹H NMR (400 MHz, CDCl₃) δ 8.63 (1H, br d, J 4 Hz), 7.74(1H, dt, J 8, 2 Hz), 7.39 (1H, br d, J 8 Hz), 7.26 (1H, m), and2.75–2.35 (8H, m)

DESCRIPTION 185 4-Isocyanato-4-(2-pyridyl)cyclohexan-1-one

4-Oxo-1-(2-pyridyl)cyclohexanecarboxyl azide (Description 184, 377 mg,1.54 mmol) in toluene (5 mL) was stirred at 90° C. for 1.25 hours,cooled and the solvent was evaporated under reduced pressure to to givethe title compound (330 mg, 99%). m/z (ES⁺) 217 (M+1).

DESCRIPTION 186 Trans-Methyl4-[4-(Phenylmethyl)piperazin-1-yl]-1-phenylcyclohexanecarboxylate

Sodium triacetoxyborohydride (10 g, 46.79 mmol) was added to a solutionof 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 17, 8.5 g,38.99 mmol) and 1-(phenylmethyl)piperazine (6.2 mL, 38.99 mmol) indichloroethane (200 mL) and the mixture was stirred at room temperaturefor 18 hours. The solvent was evaporated under reduced pressure and theresidue was triturated with methanol. The solid was collected, washedwith methanol, suspended in methanol (200 mL) and acetyl chloride (4.2mL, 58.5 mmol) was added dropwise. The mixture was heated under refluxfor 2 days, cooled and basified with saturated aqueous sodium hydrogencarbonate. The methanol was evaporated under reduced pressure and themixture was extracted with ethyl acetate. The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was crystallised from propan-2-ol (4 mL/g) to givethe title compound as a colorless solid (5.65 g, 36%). m/z (ES⁺) 393(M+1).

DESCRIPTION 187Trans-4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexanecarboxylicAcid Dihydrochloride

Trans-Methyl4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexanecarboxylate(Description 186, 5 g, 12.76 mmol) was dissolved in hydrochloric acid(5M, 150 mL) and heated under reflux for 3 days. The mixture was cooled,the solvent was evaporated under reduced pressure and the residue wasdried in vacuo to give the title compound as a colorless solid, (5.37 g,93%). m/z (ES⁺) 379 (M+1).

DESCRIPTION 188Trans-4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexylamine

Diphenylphosphoryl azide (5.1 mL, 23.75 mmol) was added to a suspensionoftrans-4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexanecarboxylicacid dihydrochloride (Description 187, 4.3 g, 9.5 mmol) andtriethylamine (6.6 mL, 47.5 mmol) in toluene (150 mL) and the mixturewas heated to 50° C. for 3 hours. The mixture was cooled, diluted withethyl acetate, washed with a saturated solution of sodium carbonate,dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was suspended in hydrochloric acid (5M, 100 mL) and the mixturewas stirred at room temperature for 24 hours. The mixture was basifiedwith aqueous sodium hydroxide (4M) and extracted with ethyl acetate. Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was dissolved in ethanol(100 mL), potassium hydroxide (10 g) was added and the mixture washeated under reflux for 4 days. The mixture was cooled, poured intowater and extracted with ethyl acetate. The combined organic fractionswere washed with water, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure to give the title compound as a brown oil (3.07g, 93%). m/z (ES⁺) 350 (M+1).

DESCRIPTION 189 1,1-Dimethylethyl 4-Oxo-1-phenylcyclohexylcarbamate

Di-tert-butyl dicarbonate (13.55 g, 62.1 mmol) was added to a solutionof 4-oxo-1-phenylcyclohexylamine (Description 18, 9.78 g, 51.7 mmol) indichloromethane (150 mL) and the mixture was stirred at room temperaturefor 18 hours, then under reflux for 6 hours. Further di-tert-butyldicarbonate (8.00 g, 36.7 mmol) was added and the mixture was stirredunder reflux for 60 hours. The mixture was cooled and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (75:25increasing to 67:33), to give the title compound as a colorless solid(8.35 g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.22 (5H, m), 5.02 (1H, brs), 2.75–2.50 (4H, m), 2.39 (2H, br d, J 12 Hz), 2.28 (2H, b. t, J 12Hz), and 1.40 (9H, br s)

DESCRIPTION 190 Trans-1,1-Dimethylethyl4-(3-Oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexylcarbamate

Sodium triacetoxyborohydride (985 mg, 4.7 mmol) was added to a solutionof 1,1-dimethylethyl 4-oxo-1-phenylcyclohexylcarbamate (Description 189,3.2 g, 11 mmol) and 1-(phenyl)piperazinone (2.1 g, 12.1 mmol) in1,2-dichloroethane (100 mL) and the mixture was stirred at roomtemperature for 19 hours. Saturated aqueous sodium hydrogen carbonate(100 mL) and water (50 mL) were added and the mixture was extracted withdichloromethane (3×50 mL). The combined organic fractions were dried(MgSO₄), the solvent was evaporated under reduced pressure and theresidue was recrystallised twice from methanol. The residue was purifiedby flash column chromatography on silica gel, eluting withisohexane/EtOAc (20:80), to give the title compound as a colorless foam(1.1 g, 23%). m/z (ES⁺) 450 (M+1).

DESCRIPTION 191 Trans-1,1-Dimethylethyl4-[3-Oxo-4-(2-chlorophenyl)-1-piperazinyl]-1-phenylcyclohexylcarbamate

Prepared from 1,1-dimethylethyl 4-oxo-1-phenylcyclohexylcarbamate(Description 189) and 1-(2-chlorophenyl)piperazinone (Tetrahedron Lett.1998, 39, 7459–7462) according to the method of Description 190. m/z(ES⁺) 484, 486 (M+1).

DESCRIPTION 192 Trans-1,1-Dimethylethyl4-[3-Oxo-4-(2-methylphenyl)-1-piperazinyl]-1-phenylcyclohexylcarbamate

Prepared from 1,1-dimethylethyl 4-oxo-1-phenylcyclohexylcarbamate(Description 189) and 1-(2-methylphenyl)piperazinone (Tetrahedron Lett.1998, 39, 7459–7462) according to the method of Description 190. m/z(ES⁺) 464 (M+1).

DESCRIPTION 193Trans-4-(3-Oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexylamine

Trifluoroacetic acid (4 mL) was added to a stirred, cooled (0° C.)solution of trans-1,1-dimethylethyl4-(3-oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexylcarbamate(Description 190, 1.0 g, 2.2 mmol) in dichloromethane (20 mL) and themixture was stirred at 0° C. for 15 minutes, then at room temperaturefor 2 hours. The solvent was evaporated under reduced pressure,saturated aqueous sodium hydrogen carbonate (50 mL) was added and themixture was extracted with dichloromethane (3×50 mL). The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure to give the title compound as a colorless foam(780 mg, 100%). m/z (ES⁺) 350 (M+1).

DESCRIPTION 194Trans-4-[3-Oxo-4-(2-chlorophenyl)-1-piperazinyl]-1-phenylcyclohexylamine

Prepared from trans-1,1-dimethylethyl4-[3-oxo-4-(2-chlorophenyl)-1-piperazinyl]-1-phenylcyclohexylcarbamate(Description 191) according to the method of Description 193. m/z (ES⁺)384,386 (M+1).

DESCRIPTION 195Trans-4-[3-Oxo-4-(2-methylphenyl)-1-piperazinyl]-1-phenylcyclohexylamine

Prepared from trans-1,1-dimethylethyl4-[3-oxo-4-(2-methylphenyl)-1-piperazinyl]-1-phenylcyclohexylcarbamate(Description 192) according to the method of Description 193. m/z (ES⁺)364 (M+1).

DESCRIPTION 196Trans-N-Ethyl-4-(3-oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexylamine

Acetaldehyde (81 μL, 1.45 mmol) was added to a solution oftrans-4-(3-oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexylamine(Description 193, 100 mg, 0.29 mmol) in methanol (2 mL) and the mixturewas stirred at room temperature for 16 hours. Sodium borohydride (57 mg,1.5 mmol) was added and the mixture was stirred at room temperature for1 hour. The solvent was evaporated under reduced pressure and saturatedaqueous sodium hydrogen carbonate (4 mL) was added. The mixture wasextracted with dichloromethane (3×15 mL) and the combined organicfractions were poured onto an SCX cartridge (Varian Bond Elut™; 10mL/500 mg). The cartridge was washed with methanol (4×2 mL), then elutedwith methanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure and the residue was purified by preparative thin layerchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(90:8:1), to give the title compound as a colorless gum (28 mg, 26%).m/z (ES⁺) 378 (M+1).

DESCRIPTION 197Trans-N-Ethyl-4-[3-oxo-4-(2-chlorophenyl)-1-piperazinyl]-1-phenylcyclohexylamine

Prepared fromtrans-4-[3-oxo-4-(2-chlorophenyl)-1-piperazinyl]-1-phenylcyclohexylamine(Description 194) according to the method of Description 196. m/z (ES⁺)412, 414 (M+1).

DESCRIPTION 198Trans-N-Ethyl-4-[3-oxo-4-(2-methylphenyl)-1-piperazinyl]-1-phenylcyclohexylamine

Prepared fromtrans-4-[3-oxo-4-(2-methylphenyl)-1-piperazinyl]-1-phenylcyclohexylamine(Description 195) according to the method of Description 196. m/z (ES⁺)392 (M+1).

DESCRIPTION 199 Cis- and trans-1,1-Dimethylethyl4-(2-Hydroxyethylamino)-1-phenylcyclohexylcarbamate

Sodium triacetoxyborohydride (1.4 g, 6.9 mmol) was added to a solutionof 1,1-dimethylethyl 4-oxo-1-phenylcyclohexylcarbamate (Description 189,1 g, 3.5 mmol) and ethanolamine (229 μL, 3.8 mmol) in 1,2-dichloroethane(10 mL) and the mixture was stirred at room temperature overnight.Saturated aqueous sodium hydrogen carbonate (3 mL) and dichloromethane(5 mL) were added and the layers were separated. The organic layer wasdried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (92:8;1), to give the title compoundas a 2:1 mixture of cis- and trans-isomers (920 mg, 79%). m/z (ES⁺) 335(M+1).

DESCRIPTION 200 Cis- and Trans-1,1-Dimethylethyl4-{N-(2-hydroxyethyl)[(2-chlorophenyl)aminocarbonylmethyl]amino}-1-phenylcyclohexylcarbamate

Cis- and trans-1,1-dimethylethyl4-(2-hydroxyethylamino)-1-phenylcyclohexylcarbamate (mixture ofdiastereoisomers, Description 199. 920 mg. 2.75 mmol) in acetonitrile(75 mL) and 2-bromo-N-(2-chlorophenyl)acetamide (2 g, 8.25 mmol) wereadded simultaneously to a suspension of potassium carbonate (2 g, 13.8mmol) in acetonitrile (50 mL) and the mixture was heated at 80° C. for16 hours. The mixture was cooled and the solvent was evaporated underreduced pressure. Dichloromethane and water were added and the layerswere separated. The organic layer was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(98:2:1) to give the title compound as a 2:1 mixture of cis- andtrans-isomers (1.03 g, 73%). ¹H NMR (400 MHz, CD₃OD) δ 1.09–1.44 (10H,m), 1.70–1.88 (5H, m), 2.37–2.68 (1H, m), 2.68–2.89 (4H, m), 3.16 and3.42 (total 2H, each s), 3.59–3.71 (2H, m), 7.07–7.51 (8H, m), and8.21–8.33 (1H, m). m/z (ES⁺) 502, 504 (M+1).

DESCRIPTION 201 Cis- and Trans-1,1-Dimethylethyl4-[4-(2-Chlorophenyl)-3-oxopiperazin-1-yl]-1-phenylcyclohexylcarbamate

Prepared as a 2:1 mixture of cis- and trans-isomers from cis- andtrans-1,1-dimethylethyl4-{N-(2-hydroxyethyl)[(2-chlorophenyl)aminocarbonylmethyl]amino}-1-phenylcyclohexylcarbamate(Mixture of diastereoisomers, Description 200) according to the methodof Example 230. m/z (ES⁺) 484, 486 (M+1).

DESCRIPTION 202Trans-4-[4-(2-Chlorophenyl)-3-oxopiperazin-1-yl]-1-phenylcyclohexylamine

Trifluoroacetic acid (1.5 mL) was added to a solution of cis- andtrans-1,1-dimethylethyl4-[4-(2-chlorophenyl)-3-oxopiperazin-1-yl]-1-phenylcyclohexylcarbamate(mixture of diastereoisomers, Description 201, 1.03 g, 2.05 mmol) indichloromethane (10 mL) and the mixture was stirred at room temperaturefor 3 hours. Saturated aqueous sodium hydrogen carbonate (3 mL) anddichloromethane (5 mL) were added and the layers were separated. Theaqueous layer was extracted with dichloromethane (3×3 mL) and thecombined organic fractions were poured onto an SCX cartridge (VarianBond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent wasevaporated under reduced pressure and the residue was purified bypreparative thin layer chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (92:8:0.8), to give the title compound (140 mg,14%). m/z (ES⁺) 384, 386 (M+1).

DESCRIPTION 203 (2R*,1′R*)- and(2S*,1′R*)-α-Methyl-N-(1-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-enyl)-3,5-bis(trifluoromethyl)benzeneacetamide

(RS)-α-Methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 638 mg, 1.4 mmol) in tetrahydrofuran (10 mL) was added to astirred, cooled (−78° C.) solution of lithium diisopropylamide intetrahydrofuran (0.1M, 30 mL). The mixture was stirred at −78° C. for 3hours, then allowed to warm to −10° C. over 30 minutes. The mixture wascooled to −78° C., then1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide(499 mg, 1.4 mmol) in tetrahydrofuran (10 mL) was added. The mixture wasallowed to warm to room temperature and stirred for 16 hours. Saturatedaqueous ammonium chloride (10 mL), water (50 mL) and ethyl acetate (50mL) were added and the layers were separated. The aqueous fraction wasextracted with ethyl acetate (2×50 mL), the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with isohexane/EtOAc (100:0 increasing to 90:10) togive the title compound as a mixture of regioisomers (540 mg, 65%). m/z(ES⁺) 590 (M+1).

DESCRIPTION 204(RS)-α,α-Dimethyl-N-{1-phenyl-4-[(trimethylsilyl)oxy]cyclohex-3-enyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 0.47 mL) wasadded to a stirred, cooled (0° C.) solution ofα,α-dimethyl-N-[4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 57, 100 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and the mixturewas stirred at 0° C. for 30 minutes. Chlorotrimethylsilane (29 μL, 0.22mmol) was added and the mixture was stirred at room temperature for 1hour. Saturated aqueous sodium hydrogen carbonate was added and themixture was extracted with ethyl acetate. The combined organic fractionswere dried (MgSO₄), filtered through alumina and the solvent wasevaporated under reduced pressure to give the title compound as a paleyellow oil (110 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (1H, s), 7.77(2H, s), 7.29–7.20 (5H, m), 5.53 (1H, s), 4.67–4.65 (1H, m), 2.80–2.74(1H, m), 2.53–2.45 (1H, m), 2.23–2.14 (1H, m), 1.97–1.93 (1H, m), 1.55(6H, s), 1.56–1.47 (1H, m), and 0.15 (9H, s).

EXAMPLE 1N-(1,4-Dioxa-8-phenylspiro[4.5]decan-8-yl)-3,5-bis(trifluoromethyl)benzeneacetamide

Oxalyl chloride (116 μl, 1.4 mmol) and dimethylformamide (1 drop) wereadded to a suspension of 3,5-bis(trifluoromethyl)benzeneacetic acid(0.38 g, 1.4 mmol) in dichloromethane (2 mL) and the mixture was stirredat room temperature for 1 hour. The solvent was evaporated under reducedpressure and toluene (10 mL) was added. The solvent was evaporated underreduced pressure and further toluene (10 mL) was added. The solvent wasevaporated under reduced pressure and a solution of1,4-dioxa-8-phenylspiro[4.5]decan-8-amine (Description 15, 80 mg, 0.34mmol) in dichloroethane (3 mL) and triethylamine (0.2 mL, 1.4 mmol) wereadded. The mixture was stirred at room temperature overnight, dilutedwith saturated aqueous sodium hydrogen carbonate and extracted withdichloromethane (3×20 mL). The combined organic fractions were washedwith brine, dried (MgSO₄) and the solvent was evaporated under reducedpressure to give the title compound as a brown gum (170 mg, 100%). m/z(ES⁺) 488 (M+1).

EXAMPLE 2N-(4-Oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Hydrochloric acid (2M, 6 mL) was added to a solution ofN-(1,4-dioxa-8-phenylspiro[4.5]decan-8-yl)-3,5-bis(trifluoromethyl)benzeneacetamide(example 1, 170 mg, 0.34 mmol) in acetone (7 mL) and the mixture wasstirred at room temperature for 16 hours. The solvent was evaporatedunder reduced pressure, aqueous sodium hydroxide was added and themixture was extracted with ethyl acetate (2×20 mL). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure to give the title compound as acolorless gum (76 mg, 49%). m/z (ES⁺) 444 (M+1).

EXAMPLE 3(RS)-α-Methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid(Description 4) and 4-oxo-1-phenylcyclohexylamine hydrochloride(Description 18) according to the method of Example 1. ¹H NMR (400 MHz,CDCl₃) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70(1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60(1H, m), and 1.52 (3H, d, J 7.0 Hz).

EXAMPLE 4Cis-(RS)-α-Methyl-N-{4-[4-Phenylmethyl-4-(dimethylamino)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamideandTrans-(RS)-α-Methyl-N-{4-[4-Phenylmethyl-4-(dimethylamino)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

A solution of sodium cyanoborohydride (6.3 mg, 100 μmol) and zincchloride (6.8 mg. 50 μmol) in methanol (1 mL) was added to a solution of(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 23 mg, 50 μmol) and4-(dimethylamino)-4-(phenylmethyl)piperidine (Description 14, 22 mg, 100μmol) in methanol (2 mL) and the mixture was stirred at room temperaturefor 2 hours. The solvent was evaporated in a stream of nitrogen, water(3 mL) and aqueous potassium carbonate (saturated, 1.5 mL) were addedand the mixture was extracted with dichloromethane (3×1.5 mL). Thecombined organic fractions were poured onto an SCX cartridge (VarianBond Eluta™; 10 mL/500 mg), and the cartridge was washed with methanol(4×1.5 mL) and eluted with methanolic ammonia (2M, 3×1.5 mL). Thesolvent was evaporated under reduced pressure and the residue waspurified by preparative thin layer chromatography on silica gel, elutingwith CH₂Cl₂/MeOH/NM(aq.) (90:10:1), to give:cis-(RS)-N-{4-[4-phenylmethyl-4-(dimethylamino)piperidin-1-yl]-phenylcyclohexyl}-3,5-bis(trifluoromethyl)-α-methylbenzeneacetamide(12 mg, 35%), ¹H NMR (400 MHz, CD₃OD) δ 7.93 (2H, s) 7.86 (1H, s),7.27–7.13 (10H, m), 4.01 (1H, q, J 7.0 Hz), 2.68 (2H, s), 2.58–2.34 (7H,m), 2.30 (6H, s), 1.84–1.64 (6H, m), 1.46 (3H, m), 1.42 (3H, d, J 7.0Hz), and 1.25 (1H, m); m/z (ES⁺) 660 (M+1); andtrans-(RS)-N-{4-[4-phenylmethyl-4-(dimethylamino)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)-α-methylbenzeneacetamide,(6 mg, 19%), ¹H NMR (400 MHz, CD₃OD) δ 7.82 (1H, s) 7.74 (2H, s),7.37–7.10 (10H, m), 3.77 (1H, q, J 7.0 Hz), 2.86 (1H, m), 2.66 (2H, s),2.68–2.29 (6H, m), 2.27 (6H, s), 1.86–1.25 (10H, m), and 1.32 (3H, d), J7.0 Hz); m/z (ES⁺) 660 (M+1).

EXAMPLE 5Cis-(RS)-α-Methyl-N-{4-[4-(phenylmethyl)-4-hydroxypiperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamideandTrans-(RS)-α-Methyl-N-{4-[4-(Phenylmethyl)-4-hydroxypiperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethylbenzeneacetamide

Prepared from(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3) and 4-(phenylmethyl)piperidin-4-ol according to the methodof Example 4:

Cis-(RS)-N-{4-[4-(Phenylmethyl)-4-hydroxypiperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)-α-methylbenzeneacetamide;¹H NMR (400 MHz, CD₃OD) δ 1.28–1.38 (1H, m), 1.44 (3H, d, J 7.0 Hz),1.50–1.54 (3H, m), 1.62–1.78 (6H, m), 1.84–1.87 (2H, m), 2.43–2.63 (8H,m), 2.75 (2H, s), 4.02 (1H, q, J 7.0 Hz), 7.11–7.29 (10H, m), 7.86 (2H,s) and 7.93 (1H, s); m/z (ES⁺) 633 (M+1);Trans-(RS)-N-{4-[4-(Phenylmethyl)-4-hydropiperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoroethyl)-α-methylbenzeneacetamide;¹H NMR (400 MHz, CD₃OD) δ 1.32 (3H, d, J 7.0 Hz), 1.41–1.49 (4H, m),1.53–1.59 (2H, m), 1.62–1.7 (2H, m), 1.75–1.90 (4H, m), 2.42–2.55 (4H,m), 2.64–2.74 (6H, m), 2.89–2.92 (1, m), 3.78 (1H, q, J 7.0 Hz),7.13–7.29 (8H, m), 7.38–7.41 (21 m), 7.75 (2H, s) and 7.79 (1H, s); m/z(ES⁺) 633 (M+1).

EXAMPLE 6Cis-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride; andTrans-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared fromN-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 2) and 4-(4-fluorophenyl)piperidine (Description 11) accordingto the method of Example 4:

Cis-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide; ¹H NMR (400 MHz, CDCl₃) δ 1.37–1.49 (2H, m), 1.69–1.87(6H, m), 1.92–1.95 (2H, m), 2.23 (2H, t, J 10.7 Hz), 2.34–2.39 (R¹, m),2.43–2.54 (3H, m), 3.04 (2H, br d, J 9.9 Hz), 3.67 (2H, s), 5.67 (1H,s), 6.95–7.01 (2H, m), 7.16–7.26 (3H, m), 7.27–7.34 (4H, m), 7.75 (2H,s) and 7.79 (1H, s); m/z (ES⁺) 607 (M+1);Trans-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide Hydrochloride; m.p. 247–250° C., ¹H NMR (400 MHz,DMSO-d₆) δ 1.42–1.55 (2H, m), 1.93–2.06 (9H, m), 2.77–2.80 (3H, m),2.90–3.02 (2H, m), 3.49 (2H, br d, J 11.5 Hz), 3.60 (2H, s), 7.14 (2H,t, J 8.8 Hz), 7.21–7.25 (3H, m), 7.31 (2H, t, J 7.5 Hz), 7.49 (2H, d, J7.9 Hz), 7.83 (2H, s), 7.94 (1H, s), 8.42 (1H, s) and 9.40 (1H, s); m/z(ES⁺) 607 (M+1).The following compounds were prepared as mixtures of cis- andtrans-isomers from(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3) according to the method of Example 4, substituting asuitable amine for 4-(dimethylamino)-4-(phenylmethyl)piperidine.

m/z (ES⁺) (M + Ex. —NR₂ Formula M.W. 1). 7

C28H32F6N2O 526 527 8

C24H26F6N2O 472 473 9

C25H28F6N2O 486 487 10

C30H30F6N2O 548 549 11

C27H30F6N2O2 528 529 12

C28H32F6N2O2 542 543 13

C30H34F6N2O3 584 585 14

C27H30F6N2O 512 513 15

C31H36F6N2O3 598 599 16

C27H30F6N2O 512 513 17

C30H37F6N3O 569 570 18

C29H34F6N2O 540 541 19

C32H32F6N2O 574 575 20

C29H34F6N2O 540 541 21

C34H34F6N4OS 660 661 22

C29H34F6N2O 540 541 23

C28H32F6N2O 526 527 24

C27H30F6N2OS 544 545 25

C29H32F6N2O 538 539 26

C26H28F6N2O3 530 531 27

C33H41F6N3O 609 610 28

C30H36F6N2O 554 555 29

C29H34F6N2O2 556 557 30

C29H34F6N2O2 556 557 31

C26H28F6N2O 498 499  32¹

C35H37F7N2O 634 635 ¹4-Fluoro-A-(phenylmethyl)piperidine: WO 97/18202

EXAMPLE 33Trans-(RS)-α-Methyl-N-{4-[(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium acetoxyborohydride (238 mg, 1.12 mmol) was added to a cooled (0°C.) solution of(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 394 mg, 0.86 mmol) and 1,1-dimethylethyl(2-aminoethyl)carbamate (166 mg, 1.03 mmol) in dichloroethane (15 mL)and the mixture was stirred at 0° C. for 1 hour, then at roomtemperature for 2 hours. Aqueous sodium hydroxide (1M, 30 mL) was addedand the mixture was extracted with dichloromethane (3×30 mL). Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was recrystallised fromisohexane/EtOAc (80:20, 10 mL). The solid was collected andrecrystallised from isohexane/EtOAc (65:35, 12 mL). The solid wascollected and dried in vacuo to give the title compound as a colorlesssolid (333 mg, 64%). m/z (ES⁺) 602 (M+1).

EXAMPLE 34Trans-(RS)-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride

Prepared fromtrans-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylamine(Description 22) and (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneaceticacid (Description 4) according to the method of Example 1. m/z (ES⁺) 621(M+1).

EXAMPLE 35Trans-(RS)-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-N,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride

Prepared fromtrans-4-[4-(4-fluorophenyl)piperidin-1-yl]-N-methyl-1-phenylcyclohexylamine(Description 24) and (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneaceticacid (Description 4) according to the method of Example 1. m/z (ES⁺) 635(M+1).

EXAMPLE 36Trans-(RS)-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride

Prepared fromtrans-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylamine(Description 22) and α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneaceticacid, (Description 6) according to the method of Example 1. m/z (ES⁺)635 (M+1).

EXAMPLE 37Trans-(RS)-N-{4-[4-(4-Fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α-hydroxymethyl-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride

1-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.6mmol) was added to a solution oftrans-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylamine(Description 22, 50 mg, 0.14 mmol), lithium(RS)-α-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate(Description 8, 110 mg, 0.2 mmol), 1-hydroxybenzotriazole (81 mg, 0.6mmol) and triethylamine (0.28 mL, 0.20 g, 2 mmol) in tetrahydrofuran (5mL) and dimethylformamide (6 mL) and the mixture was stirred at roomtemperature for 48 hours. Aqueous sodium hydrogen carbonate (saturated,30 mL) and water (30 mL) were added and the mixture was extracted withethyl acetate (2×30 mL) The combined organic fractions were washed withwater (3×20 mL) and brine (20 mL), dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃ (Aq.) (90:8:1), to give the title compound as acolorless solid (18 mg, 20%). m/z (ES⁺) 637 (M+1).

EXAMPLE 38Trans-(RS)-α-Methyl-N-[4-(4-oxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5bis(trifluoromethyl) benzeneacetamide

Prepared from trans-1-(4-amino-4-phenylcyclohex-1-yl)piperidin-4-onedihydrochloride (Description 27) and(RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4)according to the method of Example 1. ¹H NMR (400 MHz, CDCl₃) δ 7.76(1H, s), 7.65 (2H, s), 7.40–7.24 (5H, m), 5.49 (1H, s), 3.50 (1H, q, J7.0 Hz), 2.75–2.72 (4H, m), 2.66–2.55 (3H, m), 2.39–2.36 (3H, m),2.23–2.16 (2H, m), 1.75–1.69 (3H, m), 1.51–37 (2H, m), and 1.43 (3H, d,J 7.0 Hz).

EXAMPLE 39Trans-(RS)-N-(4-Amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide

Triphenylphosphine (1.5 g, 5.6 mmol) and water (2 mL) were added to asolution of crudetrans-(RS)-N-(4-azido-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide [Description 30, fromcis-(RS)-N-(4-methanesulfonyloxy-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Description 29, 1.5 g, 2.8 mmol)] in tetrahydrofuran (20 mL) and themixture was heated under reflux for 22 hours. The mixture was cooled andthe solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate (100 mL) and washed with hydrochloric acid(1M, 100 mL) and brine (100 mL), dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH(Aq.),to give the title compound as a colorless solid (0.91 g, 71%). m/z (ES⁺)459 (M+1).

EXAMPLE 40Trans-(RS)-α-Methyl-N-{1-phenyl-4-[(phenylmethyl)amino]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium triacetoxyborohydride (0.72 g, 3.4 mmol) was added to a solutionoftrans-(RS)-N-(4-amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 39, 0.78 g, 1.7 mmol) and benzaldehyde (0.17 mL, 0.18 g, 1.7mmol) in dichloroethane (25 mL) and the mixture was stirred at roomtemperature for 2 hours. The mixture was washed with aqueous sodiumhydrogen carbonate (saturated) and water, dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with EtOAc, to give thetitle compound (0.77 g, 83%). m/z (ES⁺) 549 (M+1).

EXAMPLE 41Trans-(RS)-α-Methyl-N-{4-[N-methyl(phenylmethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium cyanoborohydride (148 mg, 2.4 mmol) was added to a solution oftrans-(RS)-α-methyl-N-{1-phenyl-4-[(phenylmethyl)amino]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide (Example 40, 650 mg, 1.2 mmol) and aqueous formaldehyde(37%, 0.44 mL, 6.0 mmol) in acetonitrile (20 mL) and the mixture wasstirred at room temperature for 15 minutes. Acetic acid was added untilthe pH was neutral and the mixture was stirred at room temperature for30 minutes, adding further acetic acid to maintain neutral pH. Thesolvent was evaporated under reduced pressure and aqueous sodiumhydroxide (1M) and dichloromethane were added. The layers were separatedand the aqueous layer was extracted dichloromethane (2×). The combinedorganic fractions were washed with water and brine, dried (MgSO₄) andthe solvent was evaporated under reduced pressure to give the titlecompound (644 mg, 97%). m/z (ES⁺) 563 (M+1).

EXAMPLE 42Trans-(RS)-α-Methyl-N-(4-methylamino-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Palladium hydroxide on carbon (20%, 10 mg) was added to a mixture oftrans-(RS)-α-methyl-N-{(4-[N-methyl(phenylmethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide (Example 41, 583 mg, 1.04 mmol), hydrochloric acid (1M,2 mL) and acetic acid (2.5 mL) in ethyl acetate (25 mL) and the mixturewas shaken under an atmosphere of hydrogen (40 psi) for 18 hours. Themixture was filtered through a glass fibre pad, washing with ethylacetate, and the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate and aqueous sodium carbonate(10%) was added. The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×). The combined organic fractions werewashed with brine, dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃ (Aq.)(95:5:0.5), to give the title compound (415 mg, 84%). m/z (ES⁺) 473(M+1).

EXAMPLE 43Trans-(RS)-N-[4-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]-N-(phenylmethyl)glycineMethyl Ester

Methyl bromoacetate (28 μl, 0.31 mmol) was added to a mixture oftrans-(RS)-α-methyl-N-{1-phenyl-4-[(phenylmethyl)amino]cyclohexyl}]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 40, 84 mg, 0.15 mmol) and potassium carbonate (207 mg, 1.5mmol) in dimethylformamide (2 mL) and the mixture was stirred at 100° C.overnight. The mixture was cooled, poured into ethyl acetate (25 mL) andwashed with water (25 mL) and brine (25 mL), dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting withisohexane/EtOAc (80:20 increasing to 0:100) to give the title compound(19 mg, 20%). m/z (ES⁺) 621 (M+1).

EXAMPLE 44Trans-(RS)-N-Methyl-N-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycineMethyl Ester

Prepared fromtrans-(RS)-α-methyl-N-(4-methylamino-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 42) according to the method of Example 43. m/z (ES⁺) 545 (M+1).

EXAMPLE 45Trans-(RS)-α-Methyl-N-{4-[2-(dimethylamino)acetylamino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared fromtrans-(RS)-N-(4-amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 39) according to the method of Example 37. m/z (ES⁺) 544 (M+1).

EXAMPLE 46Trans-(RS)-N-(4-Aminomethyl-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide Hydrochloride

Raney nickel (20 mg) was added to a solution oftrans-(RS)-N-(4-cyano-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Description 31, 146 mg, 0.31 mmol) in methanolic ammonia (2M, 5 mL) andthe mixture was shaken under an atmosphere of hydrogen (40 psi) for 2hours. The mixture was filtered through Celite™, washing with ethanol,and the solvent was evaporated under reduced pressure. The residue wasdissolved in methanol (1.5 mL) and poured onto an SCX cartridge (VarianBond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent wasevaporated under reduced pressure and the residue was dissolved inEtOAc/isohexane (3:1, 4 mL). Ethereal hydrogen chloride (1M, 0.5 mL) wasadded and the solid was collected and dried in vacuo to give the titlecompound as a colorless solid (101 mg, 69%); m/z (ES⁺) 473 (M+1).

EXAMPLE 47Trans-(RS)-α-Methyl-N-(4-dimethylaminomethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride

Prepared fromtrans-(RS)-N-(4-aminomethyl-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamideExample 46) according to the method of Example 41. m/z (ES⁺) 501 (M+1).

EXAMPLE 48Trans-(RS)-α-Methyl-N-[4-(piperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

1,5-Dibromopentane (9 μl, 16 mg, 0.07 mmol)was added to a mixture oftrans-(RS)-N-(4-aminomethyl-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamidehydrochloride (Example 46, 35 mg, 0.07 mmol), potassium carbonate (36mg, 0.26 mmol) and sodium iodide (5 mg, 0.03 mmol) in dimethylformamide(10 mL) and the mixture was stirred at 100° C. for 16 hours. Ethylacetate and water were added and the layers were separated. The aqueouslayer was extracted with ethyl acetate and the combined organicfractions were washed with water and brine, dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was dissolvedin methanol (2 mL) and poured onto an SCX cartridge (Varian Bond Elut™;10 mL 500 mg). The cartridge was washed with methanol (4×2 mL), theneluted with methanolic ammonia (2M, 2×2 mL). The solvent was evaporatedunder reduced pressure and the residue was purified by preparative thinlayer chromatography on silica gel, eluting with CH₂Cl₂/MeOH/Et₃N(95:5:1), to give the title compound as a colorless solid (10 mg, 28%).m/z (ES⁺) 541 (M+1).

EXAMPLE 49Trans-(RS)-4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenyl-N-{2-[3,5-bis(trifluoromethyl)phenyl]propyl}cyclohexylamineDihydrochloride

Borane tetrahydrofuran complex (1M in tetrahydrofuran, 1 mL, 1 mmol) wasadded to a solution oftrans-(RS)-N-{4-[4-(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexyl}-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 34, 100 mg, 0.16 mmol), in tetrahydrofuran (5 mL), and themixture was stirred at room temperature for 2 hours, then under refluxfor 16 hours. The mixture was cooled and methanol (5 mL) was addedslowly. The mixture was heated under reflux for 10 minutes, cooled toroom temperature and the solvent was evaporated under reduced pressure.Methanol (5 mL) was added and the solvent was evaporated under reducedpressure. Hydrochloric acid (1M) was added and the mixture was stirredat room temperature for 1 hour. The mixture was basified with aqueoussodium hydroxide (4M) and extracted with ethyl acetate (2×25 mL). Thecombined organic fractions were washed with brine, dried (MgSO₄) and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃ (Aq.) (120:8:1), The residue was dissolved in ethanoland ethereal hydrogen chloride (1M) was added. The solvent wasevaporated under reduced pressure to give the title compound as acolorless solid (19.5 mg, 18%). m/z (ES⁺) 607 (M+1).

EXAMPLE 50(S)-α-Methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (672 mg, 2.64 mmol) wasadded to a solution of(S)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 40,500 mg, 1.76 mmol) and pyridine (284 μL, 3.52 mmol) in dichloromethane(15 mL) and the mixture was stirred at room temperature for 5 minutes.4-Oxo-1-phenylcyclohexylamine hydrochloride (Description 18, 500 mg,2.64 mmol) was added and the mixture was stirred at room temperature for48 hours. The mixture was diluted with dichloromethane and washed withsaturated aqueous sodium carbonate. The organic layer was dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withisohexane:EtOAc (65:35). The residue was crystallised twice frompropan-2-ol/water (50:50, 20 mL) and the solid was collected and driedin vacuo to give the title compound as a colorless solid (200 mg, 37%).¹H NMR (400 MHz, CDCl₃) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H m), 5.71(1H, s), 3.70 (1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04(5H, m), 1.60 (1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined bychiral HPLC (Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1mL/min; 210 nm]>99%.

EXAMPLE 51(R)-α-Methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (R)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid(Description 41) and 4-oxo-1-phenylcyclohexylamine hydrochloride(Description 18) according to the method of Example 50. ¹H NMR (400 MHz,CDCl₃) δ 7.80 (1H, s), 7.72 (2H, s), 7.29 (5H, m), 5.71 (1H, s), 3.70(1H, q, J 7.0 Hz), 2.81 (1H, m), 2.64 (1H, m), 2.47–2.04 (5H, m), 1.60(1H, m), and 1.52 (3H, d, J 7.0 Hz). e.e. [Determined by chiral HPLC(Chiralcel OD-H 250×4.6 mm i.d.; isohexane/EtOH (96:4); 1 mL/min; 210nm]>99%.

EXAMPLE 52(RS)-N-(4-Oxo-1-phenylcyclohexyl)-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (RS)-α-(2-propenyl)-3,5-bis(trifluoromethyl)benzeneaceticacid (Description 35) and 4-oxo-1-phenylcyclohexylamine hydrochloride(Description 18) according to the method of Example 1. ¹H NMR (400 MHz,CDCl₃) δ 7.80 (1H, s), 7.73 (2H, s), 7.35–7.2 (5H, m), 5.80 (1H, br s),5.75–5.63 (1H, m), 5.13–5.05 (2H, m), 3.56 (1H, dd, J 7, 6 Hz),2.90–2.80 (2H, m), 2.65–2.55 (1H, m), and 2.52–2.30 (7H, m).

EXAMPLE 53(RS)-α-Methyl-N-[1-(2-Fluorophenyl)-4-oxocyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid(Description 4) and 1-(2-fluorophenyl)-4-oxocyclohexylaminehydrochloride (Description 180) according to the method of Example 1. ¹HNMR (360 MHz, CDCl₃) δ 7.79 (1H, s), 7.68 (2H, s), 7.40–7.35 (1H, m),7.27–7.21 (1H, m), 7.14–7.10 (1H, m), 6.93–6.86 (1H, m), 5.95 (1H, s),3.71 (1H, q J 7.0 Hz), 3.08–3.00 (1H, m), 2.86–2.78 (1H, m), 2.56–2.20(6H, m), and 1.49 (3H, d, J 7.0 Hz).

EXAMPLE 54(RS)-α-Methyl-N-[1-(3-Fluorophenyl)-4-oxocyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid(Description 4) and 1-(3-fluorophenyl)-4-oxocyclohexylaminehydrochloride (Description 181) according to the method of Example 1. ¹HNMR (360 MHz, CDCl₃) δ 7.81 (1H, s), 7.73 (2H, s), 7.29–7.24 (1H, m),7.06–7.03 (1H, m), 6.97–6.94 (2H, m), 5.78 (1H, s), 3.72 (1H, q, J 7.0Hz), 2.81–2.75 (1H, m), 2.63–2.57 (1×, m), 2.44–2.24 (6H, m), and 1.53(3H, d, J 7.0 Hz).

EXAMPLE 55(RS)-α-Methyl-N-[1-(4-Fluorophenyl)-4-oxocyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid(Description 4) and 1-(4-fluorophenyl)-4-oxocyclohexylaminehydrochloride (Description 182) according to the method of Example 1. ¹HNMR (400 MHz, CDCl₃) δ 7.81 (1H, s), 7.71 (2H, s), 7.29–7.25 (2H, m),7.01–6.96 (2H, m), 5.73 (1H, s), 3.69 (1H, q, J 7.0 Hz), 2.80–2.77 (1H,m), 2.62–2.57 (1H, m), 2.44–2.28 (6H, m), and 1.51 (3H, d, J 7.0 Hz).

EXAMPLE 56(RS)-α-Methyl-N-[4-oxo-1-(2-pyridyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

4-Isocyanato-4-(2-pyridyl)cyclohexan-1-one (Description 185, 327 mg,1.51 mmol) was dissolved in hydrochloric acid (5M, 5 mL) and the mixturewas heated under reflux for 24 hours. Further hydrochloric acid (5M, 2mL) was added and the mixture was heated under reflux for 24 hours. Themixture was cooled and the solvent was evaporated under reducedpressure. Toluene (2×5 mL) was added and evaporated under reducedpressure and the residue was suspended in dichloromethane (10 mL).(RS)-α-Methyl-3,5-bis(trifluoromethyl)benzeneacetyl chloride [preparedfrom (RS)-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description4, 430 mg, 1.5 mmol), oxalyl chloride (0.65 mL, 7.45 mmol) anddimethylformamide (2 drops) in dichloromethane (10 mL), followed byevaporation of solvent under reduced pressure] in dichloromethane (10mL) then pyridine (1 mL) were added and the mixture was stirred at roomtemperature for 18 hours. Aqueous potassium carbonate (10%, 50 mL) wasadded and the mixture was extracted with dichloromethane (2×50 mL). Thecombined organic fractions were dried (Na₂SO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(97.5:2.5:0.25), to give the title compound (140 mg, 20%). m/z (ES⁺) 459(M+1).

EXAMPLE 57α,α-Dimethyl-N-[4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Oxalyl chloride (5.8 mL, 66.6 mmol) was added slowly to a solution ofα,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 6,10 g, 33.3 mmol) and dimethylformamide (1 drop) in dichloromethane (100mL) and. the mixture was stirred at room temperature for 24 hours. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in dichloromethane (20 mL) and added slowly to a solution of4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18, 8.2 g, 43.4mmol) and pyridine (5.7 mL, 66.3 mmol) in dichloromethane (100 mL). Themixture was stirred at room temperature for 24 hours, then hydrochloricacid (2M, 100 mL) was added. The layers were separated and the aqueouslayer was extracted with dichloromethane. The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatograph onsilica gel, eluting with isohexane:EtOAc (75:25), to give the titlecompound as a colorless solid (6.5 g, 41%). ¹H NMR (400 MHz, CDCl₃) δ7.83 (1H, s), 7.77 (2H, s), 7.35–7.26 (5H, m), 5.44 (1H, s), 2.70–2.66(2H, m), 2.40–2.30 (6H, m), and 1.62 (6H, s).

EXAMPLE 58(1R*,3S*)-α,α-Dimethyl-N-[3-fluoro-4-oxo-7-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

A solution of(RS)-α,α-dimethyl-N-{1-phenyl-4-[(trimethylsilyl)oxy]cyclohex-3-enyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Description 204, 1.0 g, 1.78 mmol) in acetonitrile (10 mL) was addedvia a syringe pump over 1 hour to a solution of1-chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (1.83 g, 5.34 mmol) in acetonitrile (20 mL) andthe mixture was stirred at room temperature for 30 minutes. The solventwas evaporated under reduced pressure and the residue was purified byflash column chromatography on silica gel, eluting with isohexane:EtOAc(75:25 increasing to 70:30), to give the title compound as a colorlessfoam (0.75 g, 83%). ¹H NMR (400 MHz, CDCl₃) δ 7.85 (1H, s), 7.77 (2H,s), 7.34–7.26 (3H, m), 7.20–7.18 (2H, m), 5.53 (1H, s), 4.94 (1H, dq, J47.7, 6.3 Hz), 3.46–3.40 (1H, m), 2.78–2.72 (1H, m), 2.54–2.49 (1H, m),2.43–2.27 (2H, m), 2.17–2.09 (1H, m), and 1.66 (6H, d), J 11.0 Hz).

EXAMPLE 59 Cis-(RS)- andTrans-(RS)-α,α-Dimethyl-N-(3-hydroxy-4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Osmium tetroxide (2.5% in t-butanol, 0.25 mL) was added to a mixture of(RS)-α,α-dimethyl-N-{1-phenyl-4-[(trimethylsilyl)oxy]cyclohex-3-enyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Description 204, 1.81 g, 3.33 mmol) and 4-methylmorpholine-N-oxide (487mg, 4.16 mmol) in tetrahydrofuran (20 mL) and water (8 mL) and themixture was stirred at room temperature for 24 hours. Further4-methylmorpholine-N-oxide (100 mg) and tetrahydrofuran (8 mL) wereadded and the mixture was stirred at room temperature for 4 hours.Further osmium tetroxide (2.5% in t-butanol, 0.25 mL) was added and themixture was stirred at room temperature for 2 hours. The solvent wasevaporated under reduced pressure and toluene (2×30 mL) was added andevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (70:30increasing to 50:50). The residue was further purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/EtOAc (85:15), to givethe title compound as a 4:1 mixture of diastereoisomers. ¹H NMR (400MHz, CDCl₃ major diastereoisomer) δ 7.85 (1H, s), 7.78 (2H, s),7.35–7.15 (5H, m), 5.53 (1H, br s), 4.14 (1H, dd, J 12, 6.5 Hz), 3.48(1H, br s), 3.15–3.05 (1H, m), 3.05–2.95 (1H, m), 2.58 (1H, br d, J 13Hz), 2.45 (1H, dt, J 14, 5.5 Hz), 2.16 (1H, dt, J 14, 4.6 Hz), 1.95 (1H,dd, J 13.5, 12.5 Hz), 1.64 (3H, s), and 1.63 (3H, s).The following compounds were prepared according to the method of Example33, substituting a suitable ketone for(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamideand a suitable amine for 1,1-dimethylethyl (2-aminoethyl)carbamate,followed by separation of diastereoisomers by chromatography on silicagel.

m/z (ES⁺) Ex. X A B —NR₂ Stereochemistry Formula M.W. (M + 1). 60 H Me H

Cis-(2R, 2′S)-Cis-(2S, 2′S)-Trans-(2R, 2′S)-Trans-(2S, 2′S)-C₂₈H₃₂F₆N₂O₂ 542 543  61¹ H Me H

Cis-(RS)- C₃₁H₃₈F₆N₂O 568 569  62¹ H Me H

Trans-(RS)- C₃₁H₃₈F₆N₂O 568 569 63 H Me H

Trans-(RS)- C₂₉H₃₁F₉N₂O 594 595 64 H Me H

Cis-(RS)- C₂₉H₃₄F₆N₂O₂ 556 557 65 H Me H

Trans-(RS)- C₂₉H₃₄F₆N₂O₂ 556 557 66 H Me H

Cis-(RS)-Trans-(RS)- C₂₉H₃₄F₆N₂O₂ 556 557 67 H Me H

Cis-(RS)- C₃₀H₃₆F₆N₂O₂ 570 571 68 H Me H

Trans-(RS)- C₃₀H₃₆F₆N₂O₂ 570 571 69 H Me H

Cis-RS)-Trans-(RS)- C₃₁H₃₈F₆N₂O₂ 584 585 70 H Me H

Trans-(RS)- C₃₁H₃₈F₆N₂O₂ 584 585 71 3-F Me H

Trans-(RS)- C₃₅H₃₇F₇N₂O₂ 650 651 72 H Me H

Trans-(RS)- C₃₇H₄₀F₆N₂O₃ 674 675 73 H Me H

Trans-(RR) C₃₂H₃₈F₆N₂O₃ 612 613 74 H Me H

Cis-(2R*, 3′R*,4′S*)-Cis-(2S*, 3′R*,4′S*)- C₂₉H₃₄F₆N₂O₂ 556 557 75 H MeH

Trans-(2R*4′S*)-Trans-(2S*, 3′R*,4′S*)-, 3′R*, C₂₉H₃₄F₆N₂O₂ 556 557 76 HMe H

Trans-(2R*, 3′R*,4′S*)-Trans-(2S*, 3′R*,4′S*)- C₃₀H₃₆F₆N₂O₂ 570 571 77 HMe H

Trans-(2R*, 3′R*,4′S*)-Trans-(2S*, 3′R*,4′S*)- C₂₉H₃₃F₇N₂O 558 559 78 HMe H

Cis-(2R*, 3′R*)-Cis-(2S*, 3′R*)-Trans-(2R*, 3′R*)-Trans-(2S*, 3′R*)-C₂₈H₃₂F₆N₂O₂ 542 543 79 H Me H

Cis-(2R, 3′R)-Cis-(2S, 3′R)-Trans-(2R, 3′R)-Trans-(2S, 3′R)-C₃₂H₃₈F₆N₂O₃ 612 613 80 H Me H

Trans-(2R*, 3aR*,7aR*)-Trans-(2S*, 3aR*,7aR*)- C₃₀H₃₄F₆N₂O₂ 568 569 81 HMe H

Trans-(RS) C₃₀H₃₄F₆N₂O₂ 568 569 82 H Me H

Cis-(RS)- C₃₁H₃₆F₆N₂O₂ 582 583 83 H Me H

Trans-(RS)- C₃₁H₃₆F₆N₂O₂ 582 583 84 2-F Me H

Trans-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 85 3-F Me H

Trans-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 86 4-F Me H

Cis-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 87 4-F Me H

Trans-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 88 H Me H

Cis-(RS)- C₃₃H₄₀F₆N₂O₂ 610 611 89 H Me H

Trans-(RS)- C₃₃H₄₀F₆N₂O₂ 610 611 90 H Me H

Cis-(RS)-Trans-(RS)- C₃₁H₃₄F₆N₂O₃ 596 597 91 H Me H

Cis-(RS)- C₃₁H₃₆F₆N₂O₂ 582 583 92 H Me H

Trans-(RS)- C₃₁H₃₆F₆N₂O₂ 582 583 93 H Allyl H

Cis-(RS)-Trans-(RS)- C₃₃H₃₈F₆N₂O₂ 608 609 94 H Me Me

Trans- C₃₂H₃₈F₆N₂O₂ 596 597 95 2-F Me H

Trans-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 96 3-F Me H

Trans-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 97 4-F Me H

Trans-(RS)- C₃₁H₃₅F₇N₂O₂ 600 601 98 H Me H

Cis-(RS)- C₃₃H₄₀F₆N₂O₂ 610 611 99 H Me H

Trans-(RS)- C₃₃H₄₀F₆N₂O₂ 610 611 100  3-F Me H

Trans-(RS))- C₃₃H₃₉F₇N₂O₂ 628 629 101  H Me Me

Trans- C₃₄H₄₂F₆N₂O₂ 624 625 102  H Me H

Trans-(RS)- C₃₃H₄₀F₆N₂O₂ 610 611 103  H Me H

Cis-(2R*, 4′S*)-Cis-(2S*, 4′S*)- C₃₁H₃₆F₆N₂O₃ 598 599 104  H Me H

Trans-(2R*, 4′S*)-Trans-(2S*, 4′S*)- C₃₁H₃₆F₆N₂O₃ 598 599 105  H Me H

Cis-(2R*, 5′R*,6′R*)-Cis-(2S*, 5′R*,6′R*)- C₃₁H₃₆F₆N₂O₃ 598 599 106  HMe H

Trans-(2R*, 5′R*,6′R*)-Trans-(2S*, 5′R*,6′R*)- C₃₁H₃₆F₆N₂O₃ 598 599 107 H Me H

Cis-(2R*, 5′R*,6′S*)-Cis-(2S*, 5′R*,6′S*)- C₃₁H₃₆F₆N₂O₃ 598 599 108  HMe H

Trans-(2R*, 5′R*,6′S*)-Trans-(2S*, 5′R*,6′S*)- C₃₁H₃₆F₆N₂O₃ 598 599 109 H Me H

Trans-(2R*,5′R*)-Trans-(2S*, 5′R*)- C₃₁H₃₄F₈N₂O₂ 618 619 110  H Me H

Cis-(RS)- C₃₁H₃₄F₆N₂O₃ 596 597 111  H Me H

Trans-(RS)- C₃₁H₃₄F₆N₂O₃ 596 597 112  H Me H

Cis-(R)- C₃₁H₃₄F₆N₂O₃ 596 597 113  H Me H

Trans-(R)- C₃₁H₃₄F₆N₂O₃ 596 597 114  H Me H

Cis-(RS)- C₃₃H₃₈F₆N₂O₃ 624 625 115  H Me H

Trans-(RS)- C₃₃H₃₈F₆N₂O₃ 624 625 116  H Me H

Cis-(2R*, 5′R*,6′R*)-Cis-(2S*, 5′R*,6′R*)- C₃₁H₃₄F₆N₂O₄ 612 613 117  HMe H

Trans-(2R*, 5′R*,6′R*)-Trans-(2S*, 5′R*,6′R*)- C₃₁H₃₄F₆N₂O₄ 612 613 118 H Me H

Cis-(2R*, 5′R*,6′S*)-Cis-(2S*, 5′R*,6′S*)- C₃₁H₃₄F₆N₂O₄ 612 613 119  HMe H

Trans-(2R*, 5′R*,6′S*)-Trans-(2S*, 5′R*,6′S*)- C₃₁H₃₄F₆N₂O₄ 612 613 120 H Me H

Trans-(2R*, 5′R*,6′R*)-Trans-(2S*, 5′R*,6′R*)- C₃₁H₃₃F₇N₂O₃ 614 615 121 H Me H

Trans-(RS)- C₃₅H₃₅F₇N₂O₂ 648 649 122  H Me H

Cis-(RS)- C₃₂H₃₆F₆N₂O₂ 594 595 123  H Me H

Trans-(RS)- C₃₂H₃₆F₆N₂O₂ 594 595 124  H Me H

Cis-(2R*, 6′R*)-Cis-(2S*, 6′R*)-Trans-(2R*,6′R*)-Trans-(2S*, 6′R*)-C₃₂H₃₈F₆N₂O₃ 612 613 125  H Me H

Trans-(RS)- C₃₂H₃₈F₆N₂O₂ 596 597 126  H Me H

Cis-(2R*, 5′R*)-Cis-(2S*, 5′R*)-Trans-(2R*,5′R*)-Trans-(2S*, 5′R*)-C₃₁H₃₆F₆N₂O₂ 582 583 127  H Me H

Cis-(2R*, 5′R*)-Cis-(2S*, 5′R*)-Trans-(2R*,5′R*)-Trans-(2S*, 5′R*)-C₃₁H₃₄F₆N₂O₃ 596 597 128  H Me H

Trans-(2R*,10′S*)-Trans-(2S*,10′S*)- C₃₁H₃₆F₆N₂O₃ 598 599 129²  H Me H

Trans-(RS)- C₃₀H₃₅F₆N₃O₂ 583 584 130  H Me H

Cis-(RS)- C₃₃H₃₃F₆N₃O₂ 617 618 131  H Me H

Trans-(RS)- C₃₃H₃₃F₆N₃O₂ 617 618 132  H Me H

Trans-(R)- C₃₃H₃₃F₆N₃O₂ 617 618 133  H Me H

Trans-(S)- C₃₃H₃₃F₆N₃O₂ 617 618 134  2-F Me H

Cis-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 135  2-F Me H

Trans-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 136  3-F Me H

Cis-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 137  3-F Me H

Trans-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 138  4-F Me H

Cis-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 139  4-F Me H

Trans-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 140  H Me Me

Trans- C₃₅H₃₇F₆N₃O₂ 645 646 141  H Me H

Trans-(R)- C₃₂H₃₂F₆N₄O₂ 618 619 142  H Me Me

Cis- C₃₃H₃₄F₆N₄O₂ 632 633 143  H Me Me

Trans- C₃₃H₃₄F₆N₄O₂ 632 633 144  H Me H

Trans-(RS)- C₃₂H₃₂F₆N₄O₂ 618 619 145  H Me H

Trans-(R)- C₃₂H₃₂F₆N₄O₂ 618 619 146  H Me Me

Cis- C₃₃H₃₄F₆N₄O₂ 632 633 147  H Me Me

Trans- C₃₃H₃₄F₆N₄O₂ 632 633 148  H Me H

Trans-(R)- C₃₂H₃1ClF₆N₄O₂ 652654 653655 149  H Me Me

Trans- C₃₃H₃₃ClF₆N₄O₂ 666668 667669 150  H Me H

Trans-(RS)- C₃₁H₃₁F₆N₅O₂ 619 620 151  H Me Me

Trans- C₃₂H₃₃F₆N₅O₂ 633 634 152  H Me H

Trans-(RS)- C₃₀H₃₀F₆N₄O₂S 624 625 153  H Me H

Cis-(RS)- C₃₁H₃₄F₆N₆O₂ 636 637 154  H Me H

Trans-(RS)- C₃₁H₃₄F₆N₆O₂ 636 637 155³  H Me H

Cis-(RS)-Trans-(RS)- C₂₈H₂₉F₆N₅O 565 566 156  H Me H

Cis-(RS)-Trans-(RS)- C₂₉H₃₀F₆N₄O 564 565 157  H Me H

Cis-(RS)- C₂₉H₃₀F₆N₄O 564 565 158  H Me H

Trans-(RS)- C₂₉H₃₀F₆N₄O 564 565 ¹4-(1-methylethyl)piperidine: WO9908699²1-(1-methylethyl)piperazinone: DE2519400³5,6,7,8-tetrahydro[1,2,4]Triazolo[1,5-a]pyrazine: WO9937645The following compounds were prepared from(RS)-α-methyl-N-[4-oxo-1-(2-pyridyl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 56) and 2-oxa-8-azaspiro[4.5]decane (Description 86) accordingto the method of Example 33, followed by separation of diastereoisomersby preparative HPLC on silica gel.

m/z (ES⁺) Ex. A B —NR₂ Stereochemistry Formula M.W. (M + 1). 159 Me Me

Cis-(RS)- C₃₀H₃₅F₆N₃O₂ 583 584 160 Me Me

Trans-(RS)- C₃₀H₃₅F₆N₃O₂ 583 584

EXAMPLE 161Trans-(RS)-α-Methyl-N-{4-[(2-hydroxyethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Ethanolamine (471 μL, 7.8 mmol) was added to a solution of(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 3.5 g, 7.6 mmol) in 1,2-dichloroethane (150 mL) and themixture was stirred at room temperature for 15 minutes. The mixture wascooled to 0° C., sodium triacetoxyborohydride (3.3 g, 15.6 mmol) wasadded and the mixture was stirred at room temperature for 60 hours.Saturated aqueous sodium hydrogen carbonate (100 mL) and water (100 mL)were added and the mixture was extracted with dichloromethane (3×200mL). The combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was dissolved inethanol (30 mL), ethereal hydrogen chloride (1M, 20 mL) was added andthe mixture was stirred at room temperature for 10 minutes. The solventwas evaporated under reduced pressure and ethanol (20 mL) was added andevaporated under reduced pressure. Ethyl acetate (100 mL) was added andthe mixture was heated under reflux for 1 hour. The mixture was cooledto 4° C. and aged for 16 hours. The solid was collected, washed withcold ethyl acetate and dried in vacuo at 80° C. for 2 hours to give thetitle compound as a colorless solid (1.6 g, 40%). m/z (ES⁺) 503 (M+1).

EXAMPLE 162Trans-(RS)-α-Methyl-N-[4-(3-fluoro-1,2,5,6-tetrahydro-4-methylpyrid-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide,Cis-(RS)-α-Methyl-N-[4-(3-fluoro-1,2,5,6-tetrahydro-4-methylpyrid-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamideand (2R*,4′R*)-Trans-, (2S*,4′R*)-Trans-, (2R*,4′R*)-Cis-, and(2S*,4′R*)-Cis-α-Methyl-N-[4-(3,3-difluoro-4-methylpiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide

Sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added to a solutionof (RS)-3,3-difluoro-4-methylpiperidine hydrochloride (Description 60,67 mg, 0.44 mmol),(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 150 mg, 0.33 mmol) and triethylamine (110 mL, 0.88 mmol) indichloroethane (30 mL) and the mixture was stirred at room temperaturefor 72 hours. Saturated aqueous sodium hydrogen carbonate (3 mL) anddichloromethane (5 mL) were added and the layers were separated. Theorganic fraction was poured onto an SCX cartridge (Varian Bond Elut™; 10mL/500 mg). The cartridge was washed with methanol (4×2 mL), then elutedwith methanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(95:5:1), to givetrans-(RS)-α-methyl-N-[4-(3-fluoro-1,2,5,6-tetrahydro-4-methylpyrid-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide(16 mg, 7%); ¹H NMR (360 MHz, CD₃OD) δ 1.33 (3H, d, J 6.5 Hz), 1.35–2.05(9H, m), 1.63 (3H, s), 2.36–2.63 (4H, m), 2.74–2.78 (1H, m), 2.95–3.05(1H, m), 3.83 (1H, q, J 7.2 Hz), 7.12–7.39 (5H, m), 7.79 (2H, s), and7.81 (1H, s); m/z (ES⁺) 557 (M+1);cis-(RS)-α-methyl-N-[4-(3-fluoro-1,2,5,6-tetrahydro-4-methylpyrid-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide(12 mg, 5%); ¹H NMR (400 MHz, CD₃OD) δ 1.22–1.28 (1H, m), 1.44 (3H, d, J6.8 Hz), 1.43–1.54 (1H, m), 1.62 (3H, s), 1.72–1.85 (4H, m), 2.00–2.09(2H, m), 2.42–2.61 (5H, m), 2.91–3.00 (2H, m), 4.02 (1H, q, J 6.8 Hz),7.12–7.28 (5H, m), 7.94 (2H, s), and 8.14 (1H, s);. m/z (ES⁺) 557 (M+1);(2R*,4′R*)-trans-, (2S*,4′R*)-trans-, (2R*,4′R*)-cis-, and(2S*,4′R*)-cis-α-methyl-N-[4-(3,3-difluoro-4-methylpiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamideas a mixture of diastereoisomers (13 mg, 5%); ¹H NMR (360 MHz, CD₃OD) δ1.36 (3H, d, J 7.2 Hz), 1.45 (3H, d, J 6.8 Hz), 1.53–1.83 (6H, m),1.84–1.98 (2H, m), 2.09–2.25 (2H, m), 2.37–2.51 (2H, m), 2.58–2.92 (3H,m), 2.98–3.03 (1H, m), 3.89 and 4.09 (total 1H, each q, J 7.2 Hz)},7.13–736 (5H, m), and 7.80–8.18 (3H, m); m/z (ES⁺) 577 (M+1).

EXAMPLE 163 Cis-(RS)- andTrans-(RS)-α-Methyl-N-{4-[4-hydroxymethyl-4-(methoxymethyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethylbenzeneacetamide

1,1-Dimethylethyl 2-oxa-7-azaspiro[3.5]nonane-7-carboxylate (Description69, 1.5 g, 6.57 mmol) was dissolved in methanolic hydrogen chloride (1M,400 mL), the mixture was stirred at room temperature for 4 hours, andthe solvent was evaporated under reduced pressure. A portion of theresidue (150 mg, 0.87 mmol) was dissolved in dry dichloroethane (30 mL)and(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 490 mg, 1.04 mmol) and sodium triacetoxyborohydride (379 mg,1.74 mmol) were added. The mixture was stirred at room temperatureovernight, then saturated aqueous sodium hydrogen carbonate (3 mL) anddichloromethane (5 mL) were added. The layers were separated and theorganic fraction was poured onto an SCX cartridge (Varian Bond Elut™; 10mL/500 mg). The cartridge was washed with methanol (4×2 mL), then elutedwith methanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(95:5:1), to give the title compound (45 mg, 10%). ¹H NMR (400 MHz,CD₃OD) δ 1.14 (3H, m), 1.37–1.46 (4H, m), 1.73–1.88 (4H, m), 1.92–2.08(1H, m), 2.36–2.53 (4H, m), 2.62–2.65 (1H, m), 2.86–2.88 (1H, m),3.25–3.28 (3H, s), 3.30–3.63 (6H, m) 3.74–4.01 (1H, m), 7.15–7.48 (5H,m), and 7.73–7.95 (3H, m). m/z (ES⁺) 601 (M+1).

EXAMPLE 164Trans-(RS)-α-Methyl-N-{4-({N-[(1,1-dimethylethoxy)carbonyl]-(1,1-dimethylethyl)amino}acetylamino)-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

1-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.57mmol) was added to a mixture ofN-[(1,1-dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine(Description 159, 92 mg, 0.4 mmol),trans-(RS)-N-(4-amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 39, 150 mg, 0.33 mmol), 1-hydroxybenzotriazole (135 mg, 1 mmol)and triethylamine (230 μL, 1.65 mmol) in tetrahydrofuran (5 mL) and themixture was stirred at room temperature for 16 hours. Saturated aqueoussodium hydrogen carbonate (15 mL) was added and the mixture wasextracted with ethyl acetate (3×20 mL). The combined organic fractionswere washed with brine, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by preparative thinlayer chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(200:8:1), to give the title compound as a colorless foam (220 mg, 99%).m/z (ES⁺) 672 (M+1).

EXAMPLE 165Trans-4-(RS)-α-Methyl-N-{4-{[(1,1-dimethylethyl)amino]acetylamino}-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Trifluoroacetic acid (1 mL) was added to a solution oftrans-(RS)-α-methyl-N-{4-({N-[(1,1-dimethylethoxy)carbonyl]-(1,1-dimethylethyl)amino}acetylamino)-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 164) in dichloromethane (8 mL) and the mixture was stirred atroom temperature for 2 hours. The solvent was evaporated under reducedpressure, the pH was adjusted to 12.0 with aqueous sodium hydroxide (1M)and the mixture was extracted with dichloromethane (3×10 mL). Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(120:8:1), to give the title compound as colorless foam (113 mg, 60%).m/z (ES⁺) 572 (M+1).

EXAMPLE 166Trans-(RS)-N-(4-[(2-Chloroethoxy)carbonylamino]-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide

2-Chloroethyl chloroformate (253 μL, 2.45 mmol) was added to a stirred,cooled (0° C.) solution oftrans-(RS)-N-(4-amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 39, 630 mg, 1.38 mmol) and triethylamine (770 μL, 5.5 mmol) indichloromethane (10 mL) and the mixture was stirred at 0° C. for 1 hour,then at room temperature for 1 hour. Further 2-chloroethyl chloroformate(30 μL, 0.3 mmol) was added and the mixture was stirred at roomtemperature for 10 minutes. Saturated aqueous sodium hydrogen carbonate(25 mL) was added and the mixture was extracted with dichloromethane(3×20 mL). The combined organic fractions were washed with brine, dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (75:25 increasing to 0:100), to give thetitle compound as a colorless solid (537 mg, 69%). m/z (ES⁺) 565 (M+1).

EXAMPLE 167Trans-(RS)-α-Methyl-N-[4-(2-oxo-3-oxazolidinyl)-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium hydride (60% dispersion in mineral oil, 80 mg, 2.0 mmol) wasadded to a stirred, cooled (0° C.) solution oftrans-(RS)-N-(4-[(2-chloroethoxy)carbonylamino]-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 166, 530 mg, 0.94 mmol) in dimethylformamide (4 mL) and themixture was stirred at room temperature for 20 hours. The mixture waspoured into water (200 mL) and extracted with ethyl acetate (3×100 mL).The combined organic fractions were washed with water (3×50 mL) andbrine, dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by chromatography on a short columnof silica gel, eluting with EtOAc, to give the title compound as acolorless foam (371 mg, 75%). m/z (ES⁺) 529 (M+1).

EXAMPLE 168Trans-(RS)-α-Methyl-N-[4-(2-hydroxy-N-methylethylamino)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide

Lithium borohydride (2M in tetrahydrofuran, 0.1 mL, 0.2 mmol) was addedto a solution oftrans-(RS)-N-methyl-N-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycinemethyl ester (Example 44, 35 mg, 0.064 mmol) in tetrahydrofuran/toluene(3:1, 4 mL) and the mixture was heated at 50° C. overnight. The mixturewas cooled, poured into water (25 mL), acidified with hydrochloric acid(2M) and extracted with ethyl acetate (2×25 mL). The combined organicfractions were washed with brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was dissolved in methanol(1.5 mL) and poured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500mg). The cartridge was washed with methanol (4×2 mL), then eluted withmethanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(95:5:0.5), to give the title compound (12.5 mg, 38%). m/z (ES⁺) 517(M+1).

EXAMPLE 169Trans-(RS)-α-Methyl-N-[4-(4-hydroxypiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide

Sodium borohydride (3 mg, 0.092 mmol) was added to a solution oftrans-(RS)-α-methyl-N-[4-(4-oxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 38, 50 mg, 0.092 mmol) in ethanol (3 mL) and the mixture wasstirred at room temperature for 1 hour. The mixture was carefullyquenched with saturated aqueous ammonium chloride (0.5 mL), basifiedwith aqueous sodium carbonate (10%, 10 mL) and extracted with ethylacetate (2×20 mL). The combined organic fractions were washed with brinedried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was dissolved in methanol (1.5 mL) and poured onto an SCXcartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washedwith methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2mL). The solvent was evaporated under reduced pressure and the residuewas purified by flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (95:5:0.5), to give the title compound (25 mg,50%). m/z (ES⁺) 543 (M+1).

EXAMPLE 170 (2R*,4′R*)-Trans- and(2S*,4R*)-Trans-α-Methyl-N-[4-(4-methyl-3-oxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide

1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (50 mg, 0.13mmol) was added to a solution of trans-(2R*,3′R*,4′S*)- andtrans-2S*,3′R*,4′S*)-α-methyl-N-[4-(3-hydroxy-4-methylpiperidin-1-y)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Example 75, 30 mg, 0.053 mmol) indichloromethane (5 mL) and the mixture was stirred at room temperaturefor 20 minutes. Aqueous sodium bisulfite (10%, 1 mL) was added and themixture was stirred at room temperature for 5 minutes. Saturated aqueoussodium hydrogen carbonate (2 mL) was added and the layers wereseparated. The organic fraction was poured onto an SCX cartridge (VarianBond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent wasevaporated under reduced pressure and the residue was purified bypreparative thin layer chromatography on silica gel, eluting withCH₂Cl₂/MeOH/(NH₃(Aq.) (90:10:1), to give the title compound (4 mg, 13%).m/z (ES⁺) 555 (M+1).

EXAMPLE 171Trans-(3R,2′R)-3-Methyl-1-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]-3-piperidinecarboxylicacid

Aqueous sodium hydroxide (4M, 1 mL, 4 mmol) was added to a solution oftrans-3R,2′R)-ethyl3-Methyl-1-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]-3-piperidinecarboxylate(Example 73, 50 mg, 0.08 mmol) in methanol (6 mL) and the mixture wasstirred at 60° C. for 18 hours. The mixture was cooled, acetic acid (252μL, 4.4 mmol) was added and the solvent was evaporated under reducedpressure. Toluene was added and evaporated under reduced pressure. Waterand dichloromethane were added and the layers were separated. Theorganic layer was dried (MgSO₄) and the solvent was evaporated underreduced pressure to give the title compound as a colorless solid (40 mg,86%). m/z (ES⁺) 584 (M+1).

EXAMPLE 172Trans-(RS)-4-Methyl-1-[-4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]piperidine-4-carboxylicAcid

Palladium on carbon (5%, 1 mg) was added to a solution oftrans-(RS)-phenylmethyl4-methyl-1-[4-({(1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]piperidine-4-carboxylate(Example 72, 6 mg, 9 μmol) in methanol and the mixture was shaken underan atmosphere of hydrogen (50 psi) overnight. The mixture was filteredthrough a glass fibre pad and the solvent was evaporated under reducedpressure to the title compound (6 mg, 100%). m/z (ES⁺) 585 (M+1).

EXAMPLE 173Trans-(RS)-α-Methyl-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

A mixture oftrans-(RS)-α-methyl-N-[-4-(4-oxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 38, 4.5 g, 8.3 mmol), ethylene glycol (2 mL) andp-toluenesulphonic acid (1.74 g, 9.13 mmol) in tetrahydrofuran (45 mL)was heated at 65° C. for 1 hour. The mixture was cooled, poured intoaqueous sodium carbonate (10%, 50 mL) and extracted with ethyl acetate(50 mL). The organic fraction was washed with brine, dried (MgSO₄) andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (95:5:0.5), and the residue was recrystallized fromisopropanol (60 mL) to give the title compound (1.2 g, 25%). ¹H NMR (360MHz, CDCl₃) δ 7.75 (1H, s), 7.65 (2H, s), 7.39–7.23 (5H, m), 5.47 (1H,s), 3.91 (4H, s), 3.49 (1H, q, J 7 Hz), 2.68–2.38 (7H, m), 2.17–2.04(2H, m), 1.75–1.64 (6H, m), 1.48–36 (2H, m), and 1.42 (3H, d, J 7 Hz).m/z (ES⁺) 585 (M+1).

EXAMPLE 174 Trans-(2R*,5′R*)- andTrans-(2S*,5R*)-α-Methyl-N-[4-(2-oxa-6,7-dioxo-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

4-Methylmorpholine N-oxide (11 mg, 0.08 mmol) and 4 Å molecular sieveswere added to a solution of trans-(2R*,5′R*,6′R*)- andtrans-(2S*,5′R*,6′R*)-α-methyl-N-[4-(6-hydroxy-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Example 106, 32 mg, 0.053 mmol) indichloromethane (2 mL) and the mixture was stirred at room temperaturefor 10 minutes. Tetrapropylammonium perruthenate (0.9 mg, 0.0027 mmol)was added and the mixture was stirred at room temperature for 2 hours.The mixture was filtered through Celite™, diluted with dichloromethane(10 mL), washed with aqueous sodium bisulfite (10%, 10 mL), aqueouscopper sulphate (5%, 10 mL) and brine, dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(95:5:0.5), followed by preparative HPLC (ABZ+plus 250×21.0 mm i.d.;0.1% TFA-H₂O/40% MeCN; 20 mL/min; 210 nm; 25 μl injections of a 50 mg/mLsolution in MeOH) to give the title compound (3 mg, 9%). m/z (ES⁺) 611(M+1).

EXAMPLE 175 Trans-(2R*,5′R*)- andTrans-(2S*,5′R*)-α-Methyl-N-[4-(2-oxa-6-oxo-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from trans-2R*,5′R*,6′S*)- andtrans-2S*,5′R*,6′S*)-α-methyl-N-[4-(6-hydroxy-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Example 108) according to the method ofExample 174. m/z (ES⁺) 597 (M+1).

EXAMPLE 176Trans-(RS)-α-Methyl-N-[4-(2-oxa-4-oxo-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideHydrochloride

1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (37 mg,0.083 mmol) was added to a solution of (2R*,4′R*)-trans- and(2S*,4R*)-trans-α-methyl-N-[4-(4-hydroxy-2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Example 104, 50 mg, 0.083 mmol) indichloromethane (7 mL) and the mixture was stirred at room temperaturefor 15 minutes. Aqueous sodium bisulfite (10%, 1 mL) was added and themixture was stirred at room temperature for 5 minutes. Saturated aqueoussodium hydrogen carbonate (2 mL) was added and the layers wereseparated. The organic layer was poured onto an SCX cartridge (VarianBond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent wasevaporated under reduced pressure and the residue was purified bypreparative thin layer chromatography on silica gel. The residue wassuspended in diethyl ether (5 mL) and treated with ethereal hydrogenchloride (1M, 0.1 mL). The solid was collected and dried in vacuo togive the title compound (10 mg, 20%). ¹H NMR (400 MHz, CD₃OD) δ 1.34(3H, d, J 6.8 Hz), 1.35–1.46 (4H, m), 1.48–1.58 (3H, m), 1.68–1.75 (2H,m), 1.78–1.94 (3H, m), 2.17–2.22 (2H, m), 2.37–2.39 (1H, m), 2.58–2.64(1H, m), 2.82–2.86 (3H, m), 3.81 (1H, q, J 6.8 Hz), 3.94 (1H, s), 4.01(1H, s), 7.12–7.44 (5H, m), 7.77 (2H, s), and 7.79 (1H, s). m/z (ES⁺)597 (M+1).

EXAMPLE 177Trans-(RS)-α-Methyl-N-[4-(1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Palladium on carbon (8 mg) was added to a solution oftrans-(RS)-α-methyl-N-[4-(1-oxa-9-azaspiro[5.5]undec-3-en-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 123, 20 mg, 003 mmol) in ethyl acetate (2 mL) and the mixturewas stirred under hydrogen (1 atm.) for 3 hours. The mixture wasfiltered through a glass fibre pad and the solvent was evaporated underreduced pressure to give the title compound (15 mg, 84%). ¹H NMR (360MHz, CDCl₃) δ 7.72 (1H, s), 7.67 (2H, s), 7.40–7.21 (5H, m), 3.65–3.55(3H, s), 2.85 (1H, d, J 11.6 Hz), 2.70 (5H, m), 2.12–2.02 (2H, m), 1.92(4H, d, J 13.3 Hz), 1.79 (2H, m), 1.58–1.42 (9H, m), and 1.38 (3H, d, J7 Hz). m/z (ES⁺) 597 (M+1).

EXAMPLE 178 Trans-(2R*,3′R*)- andTrans-(2R*,3S*)-α-Methyl-N-[4-(3-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideand Trans-(2R*,4′R*)- andTrans-(2R*,4′S*)-α-Methyl-N-[4-(4-hydroxy-1-oxa-9-azaspiro[5.5]undecan9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared fromtrans-(RS)-α-methyl-N-[4-(1-oxa-9-azaspiro[5.5]undec-3-en-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 123) according to the method of Description 133 to givetrans-(2R*,3′R*)- andtrans-(2R*,3′S*)-α-methyl-N-[4-(3-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideas a mixture of diastereoisomers; ¹H NMR (400 MHz, CDCl₃) δ 7.75 (1H,s), 7.64 (2H, s), 7.40–7.38 (2H, m), 7.33–7.29 (2H, m), 7.26–7.22 (1H,m), 5.60 (1H, s), 3.71–3.65 (2H, m), 3.51 (1H, q, J 7 Hz), 3.43–3.38(1H, m), 2.71 (1H, d, J 12.4 Hz), 2.62–2.38 (5H, m), 2.15–2.07 (2×, m),1.90–1.80 (6H, m), 1.70–1.59 (4H, m), 1.50–1.35 (31H, m), and 1.41 (3H,d, J 7 Hz); m/z (ES⁺) 613 (M+1); and trans-(2R*,4R*)- andtrans-(2R*4′S*)-α-4-methyl-N-[4-(4-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;¹H NMR (400 MHz, CDCl₃) δ 7.74 (1H, s), 7.64 (2H, s), 7.39–7.23 (5H, m),5.75 (1H, s), 3.97–3.90 (1H, m), 3.81–3.76 (1H, m), 3.55–3.45 (2H, m),2.84–2.62 (6H, m), 2.60–2.50 (1H, m), 2.16–2.09 (3H, m), 1.97–1.78 (7H,m), 1.53–1.41 (3H, m), 1.40 (3×, d, J 7 Hz), and 1.34–1.26 (1H, m); m/z(ES⁺) 613 (M+1).

EXAMPLE 179Trans-(RS)-α-methyl-N-[4-(1-oxa-3-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from trans-(2R*,3′R*)- andtrans-(2R*,3S*)-α-methyl-N-[4-(3-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 178) according to the method of Description 120. ¹H NMR (400MHz, CDCl₃) δ 7.75 (1H, s), 7.65 (2H, s), 7.40–7.38 (2H, m), 7.33–7.30(2H, m), 7.26–7.22 (1H, m), 5.48 (1H, s), 3.52–3.47 (2H, m), 2.67–2.64(1H, m), 2.61–2.38 (7H, m), 2.17–2.10 (2H, m), 1.86–1.38 (12H, m), and1.42 (3H, d, J 7H). m/z (ES⁺) 611 (M+1).

EXAMPLE 180Trans-(RS)-α-Methyl-N-{4-[4-(phenylmethyl)piperazin-1-yl]-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Oxalyl chloride (2.3 mL, 26.4 mmol) was added slowly to a stirred,cooled (0° C.) solution of(RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4,3.77 g, 13.2 mmol) and dimethylformamide (1 drop) in dichloromethane (50mL) and the mixture was allowed to warm to room temperature and stirredfor 1 hour. The solvent was evaporated under reduced pressure and theresidue was dissolved in dichloromethane (20 mL) and added to a stirred,cooled (0° C.) solution oftrans-4-[4-phenylmethyl)piperazin-1-yl]-1-phenylcyclohexylamine(Description 188, 3.07 g, 8.8 mmol) and triethylamine (6.1 mL, 44 mmol)in dichloromethane (50 mL). The mixture was stirred at room temperaturefor 18 hours, diluted with dichloromethane (100 mL) and washed withwater. The organic fraction was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH (95:5), togive the title compound as a light brown solid (4.4 g, 81%). ¹H NMR (400MHz, CDCl₃) δ 7.75 (1H, s), 7.65 (2H, s), 7.34–7.20 (10H, m), 5.45 (1H,br s), 3.50 (1H, q, J 7.1 Hz), 3.46 (2H, s), 2.60–2.37 (10H, m),2.32–2.22 (1H, m), 2.16–2.07 (2H, m), 1.78–1.55 (3H, m), 1.50–1.35 (1H,m), and 1.43 (3H, d, J 7.1 Hz). m/z (ES⁺) 618.

EXAMPLE 181Trans-(RS)-α-Methyl-N-[4-(piperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Palladium hydroxide on carbon (5%, 0.5 g) was added to a solution oftrans-(RS)-α-methyl-N-{4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 180, 4 g, 6.48 mmol) in ethyl acetate (20 mL) and the mixturewas shaken under an atmosphere of hydrogen (50 psi) for 24 hours. Themixture was filtered through Hyflo™ and the solvent was evaporated underreduced pressure to give the title compound as a colorless foam (1.5 g,44(%). m/z (ES⁺) 528 (M+1).

EXAMPLE 182Trans-(RS)-α-Methyl-N-[4-(4-methylpiperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Palladium hydroxide on carbon (5%, 50 mg) was added to a solution oftrans-(RS)-α-methyl-N-[4-(piperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 181, 50 mg, 0.095 mmol) and formaldehyde (2 mL) in methanol (10mL) and the mixture was shaken under an atmosphere of hydrogen (50 psi)for 24 hours. The mixture was filtered through Hyflo™ and the filtratewas poured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). Thecartridge was washed with methanol (4×2 mL), then eluted with methanolicammonia (2M, 2×2 mL). The solvent was evaporated under reduced pressureto give the title compound as a light brown solid (42 mg, 82%). ¹H NMR(400 MHz, CDCl₃) δ 7.76 (1H, s), 7.66 (2H, s), 7.38–7.21 (5H, m), 5.46(1H, s), 3.51 (1H, q, J 7.0 Hz), 2.61–2.27 (10H, m), 2.24 (3H, s),2.16–2.07 (2H, m), 1.75–1.60 (3H, m), 1.49–1.37 (1H, m), and 1.43 (3H,d, J 7.1 Hz). m/z (ES⁺) 542 (M+1).

EXAMPLE 183Trans-(RS)-α-Methyl-N-{4-[4-(1-methylethyl)piperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

A mixture of sodium cyanoborohydride (6 mg, 0.095 mmol) and zincchloride (6.5 mg, 0.0475 mmol) in methanol (2 mL) was added to asolution oftrans-(RS)-α-methyl-N-[4-(piperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 181, 50 mg, 0.095 mmol) and acetone (35 μl, 0.25 mmol) inmethanol (5 mL) and the mixture was stirred at room temperature for 18hours. The mixture was poured onto an SCX cartridge (Varian Bond Elut™;10 mL/500 mg). The cartridge was washed with methanol (4×2 mL), theneluted with methanolic ammonia (2M, 2×2 mL). The solvent was evaporatedunder reduced pressure to give the title compound as a colorless solid(50 mg (93%). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (1H, s), 7.65 (2H, s),7.38–7.21 (5H, m), 5.46 (1H, br s), 3.50 (1H, q, J 7.1 Hz), 2.61–2.58(2H, m), 2.55–2.45 (8H, m), 2.30–2.23 (1H, m), 2.17–2.09 (2H, m),1.51–1.35 (3H, m), 1.43 (3×, d, J 7.1 Hz), and 1.03 (6H, d, J 6.5 Hz).m/z (ES⁺) 570 (M+1).The following compounds were prepared fromtrans-(RS)-α-methyl-N-[4-(piperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 181) according to the method of Example 183, substituting asuitable ketone or aldehyde for acetone.

m/z (ES⁺) Ex. X A B —NR₂ Stereochemistry Formula M.W. (M + 1). 184 H MeH

Trans-(RS)- C₃₃H₄₃F₆N₃O 611 612 185 H Me H

Trans-(RS)- C₃₂H₃₉F₆N₃O₂ 611 612

EXAMPLE 186Trans-(RS)-α-Methyl-N-[4-(2-oxo-1-piperazinyl)-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Bromoacetyl bromide (104 μL, 1.2 mmol) was added dropwise to a stirred,cooled (0° C.) solution oftrans-(RS)-α-methyl-N-{4-[(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)amino]-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 33, 400 mg, 0.66 mmol) and triethylamine (368 μL, 2.6 mmol) indichloromethane (15 mL) and the mixture was stirred at 0° C. for 30minutes. Saturated aqueous sodium hydrogen carbonate (25 mL) and water(25 mL) were added and the mixture was extracted with dichloromethane(3×20 mL). The combined organic fractions were washed with aqueouscitric acid (10%, 25 mL) and saturated aqueous sodium hydrogen carbonate(25 mL), dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was dissolved in dichloromethane (10 mL) cooled to0° C. and trifluoroacetic acid (2 mL) was added. The mixture was stirredat room temperature for 2 hours, then the solvent was evaporated underreduced pressure. The residue was dissolved in dichloromethane (20 mL),triethylamine (6 mL) was added and the mixture was stirred at roomtemperature for 20 hours. The solvent was evaporated under reducedpressure, water (25 mL) was added and the pH was adjusted to 12 withaqueous sodium hydroxide (4M). The mixture was extracted withdichloromethane (3×40 mL) and the combined organic fractions were washedwith brine, dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂C₂/MeOH/NH₃(Aq.) (90:8:1), to give the titlecompound as an off-white solid (262 mg, 73%). m/z (ES⁺) 542 (M+1).

EXAMPLE 187Trans-(RS)-α-Methyl-N-[4-(4-methyl-2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Aqueous formaldehyde (38%, 22 μL, 0.3 mmol) was added to a solution oftrans-(RS)-α-methyl-N-[4-(2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 186, 15 mg, 0.03 mmol) in formic acid (1 mL) and the mixturewas stirred at 70° C. for 1 hour. The mixture was cooled and the solventwas evaporated under reduced pressure. Saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with dichloromethane(3×1 mL). The combined organic fractions were poured onto an SCXcartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washedwith methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2mL). The solvent was evaporated under reduced pressure and the residuewas purified by chromatography on silica, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (120:8:1), to give the title compound as acolorless glass (5 mg, 30%). m/z (ES⁺) 556 (M+1).

EXAMPLE 188Trans-(RS)-α-Methyl-N-{4-[4-(1-methylethyl)-2-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium triacetoxyborohydride (23 mg, 0.1 mmol) was added to a solutionoftrans-(RS)-α-methyl-N-[4-(2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 186, 10 mg, 0.02 mmol) and acetone (8 μL, 0.11 mmol) in1,2-dichloroethane (1 mL) and the mixture was stirred at roomtemperature for 19 hours. Saturated aqueous sodium hydrogen carbonate (2mL) was added and the mixture was extracted with dichloromethane (3×1mL). The combined organic fractions were poured onto an SCX cartridge(Varian Bond Elut™; 10 mL/500 mg). The cartridge was washed withmethanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2 mL). Thesolvent was evaporated under reduced pressure to give the title compound(10.2 mg, 87%). ¹H NMR (400 MHz, CD₃OD) δ 1.02 (6H, d, J 6.5 Hz), 1.31(3H, d, J 7.0 Hz), 1.46–1.56 (2H, m), 1.60–1.66 (2H, m), 1.88–1.96 (2H,m), 2.62–2.69 (3H, m), 2.77–2.81 (1H, m), 3.00–3.04 (2H, m), 3.09–3.16(3H, m), 3.75 (1H, q, J 7.0 Hz), 4.44–4.46 (1H, m), 7.16–7.18 (1H, m),7.24–7.28 (2H, m), 7.43–7.46 (2H, m), 7.72 (2H, s), and 7.78 (1H, s).m/z (ES⁺) 584 (M+1).The following compounds were prepared fromtrans-(RS)-α-methyl-N-[4-(2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 186) according to the method of Example 188, substituting asuitable ketone or aldehyde for acetone.

m/z (ES⁺) Ex. X A B —NR₂ Stereochemistry Formula M.W. (M + 1). 189 H MeH

Trans-(RS)- C₃₄H₃₅F₆N₃O₂ 631 632 190 H Me H

Trans-(RS)- C₃₂H₃₇F₆N₃O₃ 625 626 191 H Me H

Trans-(RS)- C₃₃H₄₀F₆N₄O₂ 638 639 192 H Me H

Trans-(RS)- C₃₃H₃₉F₆N₃O₂ 623 624 193 H Me H

Trans-(RS)- C₃₁H₃₅F₆N₃O₂ 595 596

EXAMPLE 194Trans-(RS)-α-Methyl-N-[4-(2-oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexyl]3,5bis(trifluoromethyl)benzeneacetamide

(1R)-[,11′-Binaphthalene]-2,2′-diylbis[diphenylphosphine (2.8 mg, 0.0045mmol) and tris[(1,2-η)-1,5-diphenyl-1,4-pentadien-3-one]palladium (4.1mg, 0.0045 mmol) were added to a degassed mixture oftrans-(RS)-α-methyl-N-[4-(2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 186, 50 mg, 0.09 mmol), iodobenzene (15 μL, 0.14 mmol) andsodium t-butoxide (12 mg, 0.13 mmol) in toluene (5 mL). The mixture wasdegassed with bubbling nitrogen and stirred at 80° C. for 4 hours.Further (1R)-[1,1′-Binaphthalene]-2,2′-diylbis[diphenylphosphine (4.0mg) and tris[(1,2-η)-1,5-diphenyl-1,4-pentadien-3-one]palladium (4.1 mg,0.0045 mmol) were added and the mixture was stirred at 80° C. for 60hours. Further iodobenzene (30 μL, 0.28 mmol), sodium t-butoxide (24 mg,0.26 mmol), (1R)-[1,1′-binaphthalene]-2,2′-diylbis[diphenylphosphine(4.0 mg) and tris[(1,2-η)-1,5-diphenyl-1,4-pentadien-3-one]palladium(4.1 mg, 0.0045 mmol) were added and the mixture was degassed withbubbling argon and stirred at 80° C. for 20 hours. The mixture wascooled, poured into brine (10 mL) and water (10 mL) and extracted withethyl acetate (2×20 mL). The combined organic fractions were washed withbrine, dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was dissolved in methanol (1.5 mL) and poured ontoan SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge waswashed with methanol (4×2 mL), then eluted with methanolic ammonia (2M,2×2 mL). The solvent was evaporated under reduced pressure and theresidue was purified by flash column chromatography on silica gel,eluting with CH₂Cl₂/MeOH (98:2), then by preparative thin layerchromatography on silica gel, eluting with CH₂Cl₂/MeOH (98:2), to givethe title compound as a colorless gum (9.1 mg, 16%). m/z (ES⁺) 618(M+1).

EXAMPLE 195Trans-(RS)-α-Methyl-N-{4-[(2-aminoethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Trifluoroacetic acid (1 mL) was added to a stirred, cooled (0° C.)solution oftrans-(RS)-α-methyl-N-{4-[(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 33, 180 mg, 0.3 mmol) in dichloromethane (10 mL) and themixture was stirred at 0° C. for 10 minutes, then at room temperaturefor 1 hour. The solvent was evaporated under reduced pressure andaqueous sodium hydroxide (1M, 25 mL) was added. The mixture wasextracted with dichloromethane (3×10 mL), the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reduced pressureto give the title compound as a colorless glass (157 mg, 100%). m/z(ES⁺) 502 (M+1).

EXAMPLE 196Trans-(RS)-α-Methyl-N-[4-(3,3-dimethyl-2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Aqueous sodium hydroxide (47%, 111 μL, 1.3 mmol), was added to astirred, cooled (5° C.) mixture oftrans-(RS)-α-methyl-N-{4-[(2-aminoethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 195, 150 mg, 0.3 mmol), acetone (44 μL, 0.6 mmol), chloroform(29 μL, 0.36 mmol) and benzyltrimethylammonium chloride (2.7 mg, 0.012mmol) in dichloromethane (2 mL) and the mixture was stirred at 5° C. for20 hours. Further acetone (440 μL, 6.0 mmol), chloroform (290 μL, 3.6mmol), benzyltrimethylammonium chloride (27 mg, 0.12 mmol) and aqueoussodium hydroxide (47%, 1.1 mL, 13 mmol) were added and the mixture wasstirred at 5° C. for 24 hours. Dichloromethane was added and the mixturewas stirred at room temperature for 1 hour. Water (20 mL) was added, thelayers were separated and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (120:8:1), to give the title compoundas a colorless solid (55 mg, 32%). m/z (ES⁺) 570 (M+1).

EXAMPLE 197Trans-(RS)-α-Methyl-N-[4-(3,3-dimethyl-2-oxo-4-phenylmethyl-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium triacetoxyborohydride (19 mg, 0.09 mmol) was added to a solutionoftrans-(RS)-α-methyl-N-[4-(3,3-dimethyl-2-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 196, 10 mg, 0.018 mmol) and benzaldehyde (20 μL, 0.2 mmol) in1,2-dichloroethane (1 mL) and the mixture was stirred at roomtemperature for 19 hours. Saturated aqueous sodium hydrogen carbonate (1mL) was added and the mixture was extracted with dichloromethane (3×1mL). The combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(120:8:1), then by flash column chromatography on silica gel, elutingwith CH₂Cl₂/MeOH (98:2), to give the title compound as a colorless glass(2.4 mg, 20%). m/z (ES⁺) 660 (M+1).

EXAMPLE 198Trans-(RS)-α-Methyl-N-[4-(2,2-dimethyl-4-phenylmethyl-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Zirconium (IV) chloride (13 mg, 0.054 mmol) was added to stirred, cooled(−10° C.) solution oftrans-(RS)-α-methyl-N-[4-(2-oxo-4-phenylmethyl-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 189, 18 mg, 0.027 mmol) in tetrahydrofuran (2 mL) and themixture was stirred at −10° C. for 30 minutes. Methyl magnesium chloride(3M in tetrahydrofuran, 60 μL, 0.16 mmol) was added and the mixture wasallowed to warm to room temperature and stirred for 16 hours. Furtherzirconium (IV) chloride (40 mg, 0.16 mmol) was added and the mixture wasstirred at room temperature for 30 minutes. Methyl magnesium chloride(3M in tetrahydrofuran, 2 mL, 6 mmol) was added and the mixture wasstirred at room temperature for 96 hours. Saturated aqueous ammoniumchloride (10 mL) was added and the mixture was extracted with ethylacetate (3×15 mL). The combined organic fractions were washed withbrine, dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(200:8:1), to give the title compound as a colorless solid (8.1 mg,46%). ¹H NMR (400 MHz, CD₃OD) δ 1.09 (6H, m), 1.31–1.34 (3H, m),1.42–1.59 (4H, m), 1.83–1.91 (2H, m), 2.08 (2H, Br s), 2.25–2.38 (2H,m), 2.41–2.53 (2H, m), 2.69–2.72 (1H, m), 2.97–3.00 (2H, m), 3.37 (2H,s), 3.73 (1H, q, J 7.0 Hz), 7.13–7.26 (8H, m), 7.41 (2H, d, J 8.0 Hz),7.72 (2H, s), and 7.78 (1H, s). m/z (ES⁺) 646 (M+1).

EXAMPLE 199Trans-(RS)-α-Methyl-N-{4-({N-[1,1-dimethylethoxy)carbonyl]-1,1-dimethylethyl)amino}ethylamino)-1-phenylcyohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

1,1-Dimethylethyl N-(1,1-dimethylethyl)-N-(2-oxoethyl)carbamate(Description 160, 86 mg, 0.4 mmol) was added to a solution oftrans-(RS)-N-(4-amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 39, 100 mg, 0.22 mmol) in methanol (3 mL) and the mixture wasstirred at room temperature for 65 hours. Sodium borohydride (30 mg, 0.8mmol) was added and the mixture was stirred at room temperature for 1hour. The solvent was evaporated under reduced pressure, saturatedaqueous sodium hydrogen carbonate (15 mL) and water (15 mL) were addedand the mixture was extracted with dichloromethane (3×20 mL). Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(200:8:1), to give the title compound as a colorless foam (120 mg, 83%).m/z (ES⁺) 658 (M+1).

EXAMPLE 200Trans-(RS)-α-Methyl-N-{4-[4-(1,1-dimethylethyl)-2-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Bromoacetyl bromide (28 μL, 0.32 mmol) was added to a stirred, cooled(0° C.) solution oftrans-(RS)-α-methyl-N-{4-({N-[(1,1-dimethylethoxy)carbonyl]-(1,1-dimethylethyl)amino}ethylamino)-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 199, 118 mg, 0.18 mmol) and triethylamine (100 μL, 0.72 mmol)in dichloromethane (5 mL) and the mixture was stirred at 0° C. for 1hour. Saturated aqueous sodium hydrogen carbonate (10 mL) and water (10mL) were added and the mixture was extracted with dichloromethane (2×20mL). The combined organic fractions were washed with aqueous citric acid(10%, 20 mL) and saturated aqueous sodium hydrogen carbonate (20 mL),dried (MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2mL) was added and the mixture was stirred at room temperature for 45minutes. The solvent was evaporated under reduced pressure,dichloromethane (5 mL) and triethylamine (3 mL) were added and themixture was stirred at room temperature for 20 hours. The solvent wasevaporated under reduced pressure, water (25 mL) was added and the pHwas adjusted to 12 with aqueous sodium hydroxide (4M). The mixtures wasextracted with dichloromethane (3×20 mL), the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (120:8:1), then bypreparative thin layer chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (200:8:1), to give the title compound as acolorless glass (13 mg, 12%). ¹H NMR (400 MHz, CD₃OD) δ 1.05 (9H, s),1.31 (3H, d, J 7.0 Hz), 1.42–1.64 (4H, m), 1.88–1.98 (2H, m), 2.66 (2H,t, J 5.2 Hz), 2.76–2.84 (1H, m), 2.99–3.01 (2H, m), 3.08–3.18 (1H, m),3.30 (2H, s), 3.75 (1H, q, J 7.0 Hz), 4.39–4.49 (1H, m), 7.18 (1H, t, J7.3 Hz), 7.24–78 (2H, m), 7.43–7.45 (2H, m), 7.72 (2H, s), and 7.78 (1H,s). m/z (ES⁺) 598 (M+1).

EXAMPLE 201Trans-(RS)-N-(2-{[(1,1-Dimethylethoxy)carbonyl]amino}ethyl)-N-[4-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycineMethyl Ester

Methyl bromoacetate (24 μL, 0.25 mmol) was added to a mixture oftrans-(RS)-α-methyl-N-{4-[(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 33, 50 mg, 0.08 mmol) and potassium carbonate (69 mg, 0.5 mmol)in dimethylformamide (2 mL) and the mixture was stirred at roomtemperature for 20 hours. The mixture was diluted with water (20 mL) andextracted with ether (2×40 mL). The combined organic fractions werewashed with water (4×10 mL) and brine (20 mL), dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give crude titlecompound as a colorless solid (60 mg). m/z (ES⁺) 674 (M+1).

EXAMPLE 202Trans-(RS)-α-Methyl-N-[4-(3-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Trifluoroacetic acid (0.5 mL) was added to a solution of crudetrans-(RS)-N-(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)-N-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycinemethyl ester (Example 201, 60 mg, 0.08 mmol) in dichloromethane (3 mL)and the mixture was stirred at room temperature for 20 hours. Furthertrifluoroacetic acid (1 mL) was added and the mixture was stirred atroom temperature for 3 hours. The solvent was evaporated under reducedpressure, saturated aqueous potassium carbonate was added and themixture was extracted with dichloromethane. The combined organicfractions were dried (MgSO₄) and the solvent was evaporated underreduced pressure The residue was purified by flash column chromatographyon silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (120:8:1), to give thetitle compound as a colorless solid (20 mg, 46%). m/z (ES⁺) 542 (M+1).

EXAMPLE 203Trans-(RS)-α-Hydroxy-α-methyl-N-[4-(3-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium hydride (60% dispersion in mineral oil, 18 mg, 0.45 mmol) wasadded to a stirred, cooled (0° C.) solution oftrans-(RS)-α-methyl-N-[4-(3-oxo-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 202, 100 mg, 0.18 mmol) in dimethylformamide (2 mL) and themixture was stirred at 0° C. for 10 minutes. 2-Bromopropane (17 μL, 0.18mmol) was added and the mixture was stirred at 50° C. for 18 hours.Further sodium hydride (60% dispersion in mineral oil, 18 mg, 0.45 mmol)and 2-bromopropane (17 μL, 0.18 mmol) were added the mixture was stirredat 70° C. for 3 hours. The mixture was cooled, diluted with water (50mL) and extracted with ethyl acetate (2×25 mL). The combined organicfractions were washed with water (3×15 mL) and brine (15 mL), dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by preparative thin layer chromatography on silicagel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (200:8:1), to give the titlecompound as a yellow gum (6.5 mg, 7%). m/z (ES⁺) 558 (M+1).

EXAMPLE 204Trans-(RS)-N-(2-{N-[(1,1-Dimethylethoxy)carbonyl]-1,1-dimethylethylamino}ethyl)-N-[4-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycineMethyl Ester

Methyl bromoacetate (74 μL, 0.78 mmol) was added to a mixture oftrans-(RS)-α-methyl-N-{4-({N-[(1,1-dimethylethoxy)carbonyl]-(1,1-dimethylethyl)amino}ethylamino)-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 199, 170 mg, 0.26 mmol) and potassium carbonate (215 mg, 1.56mmol) in dimethylformamide (4 mL) and the mixture was stirred at roomtemperature for 17 hours. The mixture was diluted with water (50 mL) andextracted with ether (3×40 mL). The combined organic fractions werewashed with water (4×10 mL) and brine (15 mL), dried (MgSO₄) and thesolvent was evaporated under reduced pressure to give the title compoundas a colorless foam (192 mg, 100%). m/z (ES⁺) 674 (M+1).

EXAMPLE 205Trans-(RS)-α-Methyl-N-{4-[4-(1,1-dimethylethyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Trifluoroacetic acid (2 mL) was added to a solution oftrans-(RS)-N-(2-{N-[(1,1-dimethylethoxy)carbonyl]-1,1-dimethylethylamino}ethyl)-N-[4-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]glycinemethyl ester (Example 204, 190 mg, 0.7 mmol) in dichloromethane (5 mL)and the mixture was stirred at room temperature for 2 hours. Furthertrifluoroacetic acid (2 mL) was added and the mixture was stirred atroom temperature for 1.5 hours. The solvent was evaporated under reducedpressure, dichloromethane (5 mL) and triethylamine (2 mL) were added andthe mixture was stirred at room temperature for 20 hours. The solventwas evaporated under reduced pressure, methanol (5 mL) and triethylamine(1 mL) were added and the mixture was stirred under reflux for 3 hours,then at room temperature for 60 hours. The solvent was evaporated underreduced pressure, toluene (5 mL) was added and the mixture was heatedunder reflux for 20 hours. The mixture was cooled and the solvent wasevaporated under reduced pressure. Saturated aqueous sodium hydrogencarbonate (10 mL) and water (10 mL) were added and the mixture wasextracted with dichloromethane (3×15 mL). The combined organic fractionswere washed with brine, dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was dissolved in methanol (4 mL),sodium methoxide (7M in methanol, 60 μL, 0.4 mmol) was added and themixture was stirred at room temperature for 2 hours. Further sodiummethoxide (7M in methanol, 1 mL, 7 mmol) was added and the mixture wasstirred at room temperature for 20 hours. Further sodium methoxide (7Min methanol, 2 mL, 14 mmol) was added and the mixture was stirred at 50°C. for 3 hours and at room temperature for 20 hours. The solvent wasevaporated under reduced pressure,1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (672 mg, 3.5mmol), 1-hydroxybenzotriazole (797 mg, 5.9 mmol), triethylamine (1.4 mL,10 mmol) and tetrahydrofuran (15 mL) were added and the mixture wasstirred at room temperature for 16 hours. The solvent was evaporatedunder reduced pressure, saturated aqueous sodium hydrogen carbonate (25mL) was added and the mixture was extracted with dichloromethane (3×20mL). The combined organic fractions were washed with brine, dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (200:8:1), and the residue wasdissolved in methanol (1.5 mL) and poured onto an SCX cartridge (VarianBond Elut™; 10 mL/500 mg). The cartridge was washed with methanol (4×2mL), then eluted with methanolic ammonia (2M, 2×2 mL). The solvent wasevaporated under reduced pressure to give the title compound as acolorless foam (33 mg, 8%). m/z (ES⁺) 598 (M+1).

EXAMPLE 206Trans-(RS)-α-Methyl-N-(4-{N-[2-(4-fluorophenyl)amino-2-oxoethyl]-(2-hydroxyethyl)amino}-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Bromoacetyl bromide (1.1 mL, 12.6 mmol) was added slowly to a stirred,cooled (0° C.) mixture of 4-fluorobenzenamine (1 mL, 10.5 mmol) indichloromethane (10 mL) and aqueous potassium hydrogen carbonate (20%,10 mL) and the mixture was stirred at 0° C. for 10 minutes, then at roomtemperature for 1 hour. The mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×50 mL). The combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reduced pressureto give a purple solid (2.2 g). A sample (86 mg, 0.37 mmol),trans-(RS)-α-methyl-N-{4-[(2-hydroxyethyl)amino]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 161, 100 mg, 0.19 mmol) and potassium carbonate (131 mg, 0.95mmol) were suspended in acetonitrile (5 mL) and heated under reflux for20 hours. The mixture was cooled, diluted with water (20 mL) andextracted with dichloromethane (3×20 mL). The aqueous layer wasevaporated under reduced pressure and extracted with dichloromethane(3×20 mL). The combined organic fractions were dried (MgSO₄), thesolvent was evaporated under reduced pressure and the residue waspurified by flash column chromatography on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (200:8:1). The residue was dissolved in methanol(1.5 mL) and poured onto an SCX cartridge (Varian Bond Elut™; 10 ml/500mg). The cartridge was washed with methanol (4×2 mL), then eluted withmethanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure to give the title compound as a colorless glass (114mg, 92%). m/z (ES⁺) 654 (M+1).The following compounds were prepared according to the method of Example206, substituting a suitable amine for 4-fluorobenzenamine.

m/z (ES⁺) Ex. X A B —NR₂ Stereochemistry Formula M.W. (M + 1). 207 H MeH

Trans-(RS)- C₃₄H₃₇F₆N₃O₃ 649 650 208 H Me H

Trans-(RS)- C₃₄H₃₇F₆N₃O₃ 649 650 209 H Me H

Trans-(RS)- C₃₄H₃₇F₆N₃O₃ 649 650 210 H Me H

Trans-(RS)- C₃₅H₃₉F₆N₃O₃ 663 664 211 H Me H

Trans-(RS)- C₃₅H₃₉F₆N₃O₃ 663 664 212 H Me H

Trans-(RS)- C₃₅H₃₉F₆N₃O₃ 663 664 213 H Me H

Trans-(RS)- C₃₅H₃₉F₆N₃O₃ 663 664 214 H Me H

Trans-(RS)- C₃₅H₃₉F₆N₃O₃ 663 664 215 H Me H

Trans-(RS)- C₃₆H₄₁F₆N₃O₃ 677 678 216 H Me H

Trans-(RS)- C₃₄H₃₄F₉N₃O₃ 703 704 217 H Me H

Trans-(RS)- C₃₄H₃₄F₉N₃O₃ 703 704 218 H Me H

Trans-(RS)- C₃₄H₃₄F₉N₃O₃ 703 704 219 H Me H

Trans-(RS)- C₃₄H₃₇F₆N₃O₄ 665 666 220 H Me H

Trans-(RS)- C₃₄H₃₇F₆N₃O₄ 665 666 221 H Me H

Trans-(RS)- C₃₄H₃₇F₆N₃O₄ 665 666 222 H Me H

Trans-(RS)- C₃₄H₃₄F₉N₃O₄ 719 720 223 H Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₅ 693 694 224 H Me H

Trans-(RS)- C₃₃H₃₄F₇N₃O₃ 653 654 225 H Me H

Trans-(RS)- C₃₃H₃₄ClF₆N₃O₃ 669671 670672 226 H Me H

Trans-(RS)- C₃₃H₃₄ClF₆N₃O₃ 669671 670672 227 H Me H

Trans-(RS)- C₃₃H₃₄ClF₆N₃O₃ 669671 670672 228 H Me H

Trans-(RS)- C₃₃H₃₃Cl₂F₆N₃O₃ 703705 704706 229 H Me H

Trans-(RS)- C₃₄H₃₇F₆N₃O₃ 649 650

EXAMPLE 230Trans-(RS)-α-Methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Di-t-butyl diazenedicarboxylate (76 mg, 0.33 mmol) was added to astirred, cooled (0° C.) solution oftrans-(RS)-α-methyl-N-(4-{N-[2-(4-fluorophenyl)amino-2-oxoethyl]-(2-hydroxyethyl)amino}-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 206, 72 mg, 0.11 mmol) and triphenylphosphine (86 mg, 0.33mmol) in ethyl acetate (3 mL) and the mixture was stirred at 0° C. for15 minutes, then at room temperature for 2 hours. Saturated aqueoussodium hydrogen carbonate (10 mL) and water (10 mL) were added and themixture was extracted with ethyl acetate (2×20 mL). The combined organicfractions were poured onto an SCX cartridge (Varian Bond Elut™; 10mL/500 mg). The cartridge was washed with methanol (4×2 m), then elutedwith methanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(200:8:1), then by preparative thin layer chromatography on silica gel,eluting with isohexane/EtOAc (25:75), to give the tide compound as acolorless foam (15 mg, 21%). ¹H NMR (400 MHz, CD₃OD) δ 1.38 (3H, d, J7.0 Hz), 1.52–1.59 (1H, m), 1.66–1.75 (2H, m), 1.71–1.90 (1H, m),1.99–2.09 (2H, m), 2.39–2.47 (2H, m), 2.58–2.61 (1H, m), 2.87 (2H, t, J5.3 Hz), 3.65 (2H, t, J 5.3 Hz), 3.90 (1H, q, J 7.0 Hz), 7.11–7.18 (3H,m), 7.22–7.26 (2H, m), 7.28–7.34 (2H, m), 7.36–7.38 (2H, m), and 7.84(3H, s). m/z (ES⁺) 636 (M+1).The following compounds were prepared from the compounds of Example207–229 according to the method of Example 230.

m/z (ES⁺) Ex. X A B —NR₂ Stereochemistry Formula M.W. (M + 1). 231 H MeH

Trans-(RS)- C₃₄H₃₅F₆N₃O₂ 631 632 232 H Me H

Trans-(RS)- C₃₄H₃₅F₆N₃O₂ 631 632 233 H Me H

Trans-(RS)- C₃₄H₃₅F₆N₃O₂ 631 632 234 H Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646 235 H Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646 236 H Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646 237 H Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646 238 H Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646 239 H Me H

Trans-(RS)- C₃₆H₃₉F₆N₃O₂ 659 660 240 H Me H

Trans-(RS)- C₃₄H₃₂F₉N₃O₂ 685 686 241 H Me H

Trans-(RS)- C₃₄H₃₂F₉N₃O₂ 685 686 242 H Me H

Trans-(RS)- C₃₄H₃₂F₉N₃O₂ 685 686 243 H Me H

Trans-(RS)- C₃₄H₃₅F₆N₃O₃ 647 648 244 H Me H

Trans-(RS)- C₃₄H₃₅F₆N₃O₃ 647 648 245 H Me H

Trans-(RS)- C₃₄H₃₅F₆N₃O₃ 647 648 246 H Me H

Trans-(RS)- C₃₄H₃₂F₉N₃O₃ 701 702 247 H Me H

Trans-(RS)- C₃₅H₃₅F₆N₃O₄ 675 676 248 H Me H

Trans-(RS)- C₃₃H₃₂F₇N₃O₂ 635 636 249 H Me H

Trans-(RS)- C₃₃H₃₂ClF₆N₃O₂ 651653 652654 250 H Me H

Trans-(RS)- C₃₃H₃₂ClF₆N₃O₂ 651653 652654 251 H Me H

Trans-(RS)- C₃₃H₃₂ClF₆N₃O₂ 651653 652654 252 H Me H

Trans-(RS)- C₃₃H₃₁Cl₂F₆N₃O₂ 685687 686688 253 H Me H

Trans-(RS)- C₃₄H₃₅F₆N₃O₂ 631 632

EXAMPLE 254Trans-(R)-α-Methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamideandTrans-(S)-α-Methyl-N-{4-[4-(4-fluorophenyl-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Racemictrans-(RS)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 249) was separated by preparative chiral HPLC [Chiralcel OD-H,250×4.6 mm i.d.; isohexane/EtOH (95:5); 1 mL/min; 210 nm] to givetrans-(R)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;m/z (ES⁺) 652 (M+1); andtrans-(S)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;m/z (ES⁺) 652 (M+1).The following compounds were prepared from according to the method ofExample 1, substituting a suitable acid for3,5-bis(trifluoromethyl)benzeneacetic acid and a suitable amine for1,4-dioxa-8-phenylspiro[4.5]decan-8-amine.

m/z (ES⁺) Ex. R A B —NR₂ Stereochemistry Formula M.W. (M + 1). 255 H MeMe

Trans- C₃₄H₃₅F₆N₃O₂ 631 632 256 H Et Et

Trans- C₃₆H₃₉F₆N₃O₂ 659 660 257 H —CH₂CH₂—

Trans- C₃₄H₃₃F₆N₃O₂ 629 630 258 H CH₂OMe H

Trans-(RS)- C₃₄H₃₅F₆N₃O₃ 647 648 259 H Me Me

Trans- C₃₄H₃₄ClF₆N₃O₂ 665667 666668 260 H H H

Trans- C₃₂H₃₀ClF₆N₃O₂ 637639 638640 261 Et Me H

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646 262 Et Me H

Trans-(RS)- C₃₆H₃₉F₆N₃O₂ 659 660 263 Et Me H

Trans-(RS)- C₃₅H₃₆ClF₆N₃O₂ 679681 680682

EXAMPLE 264 Trans-(RS)-Methyl3-[-4-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexylamino]propanoate

Methyl acrylate (218 μL, 2.42 mmol) in methanol (2 mL) was addeddropwise to a stirred, cooled (0° C.) solution oftrans-(RS)-N-(4-amino-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamide(Example 39, 1.0 g, 2.2 mmol) in methanol (5 mL) and the mixture wasstirred at room temperature for 16 hours. The solvent was evaporatedunder reduced pressure to give the title compound as a foam (1.2 g,97%). m/z (ES⁺) 544 (M+1).

EXAMPLE 265 Trans-(RS)-Methyl3-{N-(3-Methoxy-1,3-dioxopropyl-[4-({1-oxo-2-[3,5-bis)trifluoromethylphenyl]propyl}amino)-4-phenylcyclohexyl]amino}propanoate

Dimethyl malonate (5 mL) was added to trans-(RS)-methyl3-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexylamino]propanoate(Example 264) and the mixture was stirred at 160–170° C. for 2 hours,then at room temperature for 16 hours. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc (50:50increasing to 0:100) to give the title compound as a colorless foam (823mg, 95%). m/z (ES⁺) 645 (M+1).

EXAMPLE 266Trans-(RS)-α-Methyl-N-[4-(2,4-dioxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium hydride (60% dispersion in mineral oil, 56 mg, 1.4 mmol) wasadded to a solution of trans-(RS)-methyl3-{N-(3-methoxy-1,3-dioxopropyl)-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]amino}propanoate(Example 265, 820 mg, 1.27 mmol) in toluene (5 mL) and the mixture wasstirred at room temperature for 1 hour. Further sodium hydride (60%dispersion in mineral oil, 56 mg, 1.4 mmol) was added and the mixturewas stirred at room temperature for 15 minutes, then under reflux for 3hours. The mixture was cooled, the solvent was evaporated under reducedpressure and aqueous acetic acid (10%, 20 mL) was added. The mixture washeated under reflux for 4 hours, cooled and the pH was adjusted to 12.0with saturated aqueous sodium hydrogen carbonate. The mixture wasextracted with dichloromethane (3×40 mL), the combined organic fractionswere dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with EtOAc, to give the title compound as acolorless foam (301 mg, 43%). m/z (ES⁺) 555 (M+1).

EXAMPLE 267Trans-(RS)-α-Methyl-N-{4-[2-oxo-4-(piperidin-1-yl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Piperidine hydrochloride (4.4 mg, 0.04 mmol) was added to a solution oftrans-(RS)-α-methyl-N-[4-(2,4-dioxopiperidin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 266, 20 mg, 0.04 mmol) in methanol (1 mL) and the mixture wasstirred at room temperature for 48 hours. Further piperidine (4 μL, 0.04mmol) and acetic acid (1 drop) were added and the mixture was stirred atroom temperature for 20 hours. Further piperidine (4 μL, 0.04 mmol) andacetic acid (1 drop) were added and the mixture was stirred at roomtemperature for 96 hours. The solvent was evaporated under reducedpressure and toluene was added and evaporated under reduced pressure.The residue was dissolved in acetic acid (2 mL), palladium on carbon(5%, 20 mg) was added and the mixture was stirred under an atmosphere ofhydrogen (1 Atm.) for 16 hours. The mixture was filtered and poured ontoan SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge waswashed with methanol (4×2 mL), then eluted with methanolic ammonia (2M,2×2 mL). The solvent was evaporated under reduced pressure and theresidue was purified by preparative thin layer chromatography on silicagel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.) (200:8:1), to give the titlecompound as a colorless glass (1.4 mg, 6%). ¹H NMR (360 MHz, CD₃OD) δ0.88–4.91 (5H, m), 1.28–1.65 (10H, m), 1.86–1.94 (2H, m), 2.05–2.08 (1H,m), 2.33–2.40 (1H, m), 2.55–2.72 (4H, m), 2.77–2.81 (2H, m), 2.92–3.13(3H, m), 3.75 (1H, q, J 7.0 Hz), 4.46 (1H, m), 7.18 (1H, t, J 7.2 Hz),7.24–7.29 (1H, m), 7.44–7.46 (2H, m), 7.72 (2H, s), and 7.78 (1H, s).m/z (ES⁺) 624 (M+1).

EXAMPLE 268Trans-(RS)-α-Methyl-N-[4-(4-oxopiperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide

Trans-(RS)-N-(4-Aminomethyl-1-phenylcyclohexyl)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetamidehydrochloride (Example 46, 40 mg, 0.074 mmol) in methanol (1 mL) and1,5-dichloropentan-3-one (11 mg, 0.074 mmol) in methanol (1 mL) wereadded simultaneously to a refluxing suspension of sodium carbonate (25mg, 0.1 mmol) in methanol over 30 minutes. The mixture was heated underreflux for 2 hours, cooled and the solvent was evaporated under reducedpressure. Dichloromethane and water were added and the layers wereseparated. The organic fraction was dried (MgSO₄) and the solvent wasevaporated under reduced pressure The residue was dissolved in methanol(1.5 mL) and poured onto an SCX cartridge (Varian Bond Elut™; 10 mL/500mg). The cartridge was washed with methanol (4×2 mL), then eluted withmethanolic ammonia (2M, 2×2 mL). The solvent was evaporated underreduced pressure and the residue was purified by preparative thin layerchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(96:4:1), to give the title compound (23 mg, 56%). ¹H NMR (400 MHz,CDCl₃) δ 1.43 (3H, d, J 8.8 Hz), 1.67–1.81 (6H, m), 2.09–2.22 (4H, m),2.36–2.40 (4H, m), 2.41–2.58 (2, m), 2.63–2.68 (3H, m), 4.10–4.35 (1,m), 7.20–7.42 (5H, m), 7.68 (2H, s), and 7.78 (1H, s). m/z (ES⁺) 555(M+1).

EXAMPLE 269Trans-(RS)-α-Methyl-N-[4-(4-hydroxypiperidin-1-yl)-methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide

Sodium borohydride (6 mg, 0.36 mmol) was added to a solution oftrails-(RS)-α-methyl-N-[4-(4-oxopiperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide(Example 268, 20 mg, 0.036 mmol) in methanol (1 mL) and the mixture wasstirred at room temperature for 1 hour. The solvent was evaporated underreduced pressure and the residue was purified by preparative thin layerchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(92:8:1), to give the title compound (15 mg, 73%). ¹H NMR (400 MHz,CDCl₃) δ 1.08–1.42 (5H, m), 1.36 (3H, d, J 6.8 Hz), 1.50–2.38 (12H, m),2.48–2.56 (1H, m), 2.72–2.77 (2H, m), 3.57–3.59 (1H, m), 3.83–3.90 (1H,m), 7.09–7.40 (5H, m), and 7.81 (3H, s). m/z (ES⁺) 557 (M+1).

EXAMPLE 270(RS)-α-Methyl-N-(4-methylene-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

n-Butyllithium (1.6 Mol solution in hexanes, 10.3 mL) was added slowlyto a stirred, cooled (0° C.) suspension of methyl triphenylphosphoniumbromide (5.86 g, 16.4 mmol) in tetrahydrofuran (60 mL) and the mixturewas stirred at room temperature for 3 hours. The mixture was cooled to0° C. and(RS)-α-methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 3.0 g, 6.56 mmol) in tetrahydrofuran (20 mL) was added. Themixture was stirred at room temperature for 1 hour, then under refluxfor 3 hours. The mixture was cooled, poured into water and extractedwith ethyl acetate. The combined organic fractions were dried (MgSO₄)and the solvent was evaporated under reduced pressure. The residue waspurified by chromatography on a short column of silica gel, eluting withdichloromethane, to give the title compound as a colorless solid (2.27g, 91%). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (1H, s), 7.75 (2H, s), 7.26–7.20(5H, m), 5.59 (1H, s), 4.68 (2H, m), 3.70 (1H, d, J 7.1 Hz), 2.53–2.45(1H, m), 2.38–2.31 (1H, m), 2.29–2.04 (4H, m), 2.00–1.85 (2H, m), and1.52 (3H, d, J, 7.1 Hz).

EXAMPLE 271 Cis-(RS) andTrans-(RS)-α-Methyl-N-(4-hydroxymethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 12 mL, 12 mmol)was added to a solution of(RS)-α-methyl-N-(4-methylene-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 270, 2.0 g, 7.84 mmol) in tetrahydrofuran (50 mL) and themixture was stirred at room temperature overnight. Aqueous sodiumhydroxide (4M, 9.8 mL) and aqueous hydrogen peroxide (30%, 9.8 mL) wereadded and the mixture was stirred at room temperature for 3 hours. Waterwas added and the mixture was extracted with ethyl acetate. The combinedorganic fractions were dried (MgSO₄) and the solvent was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (50:50increasing to 20:80), to give the title compound as a colorless solid(1.5 g, 40%) as a 1:1 mixture of cis and trans isomers. ¹H NMR (400 MHz,CD₃OD) δ 8.13 (1H, s), 8.05 (1H, s), 7.93 (2H, s), 7.86 (1H, s), 7.81(3H, s), 7.36–7.33 (2H, m), 7.27–7.11 (8H, m), 4.03 (1H, q, J 7.0 Hz),3.86 (1H, q, J 7.0 Hz), 3.39–3.37 (2H, m), 3.32–3.26 (4H, m), 2.58–2.43(3H, m), 2.39–2.32 (1H, m), 1.99–1.92 (2H, m), 1.77–1.58 (6H, m),1.52–1.49 (1H, m), 1.45 (3H, d, J 7.0 Hz), 1.37 (3H, d, J 7.0 Hz),1.31–1.29 (1H, m), 1.25–1.15 (1H, m), and 1.02–0.96 (1H, m).

EXAMPLE 272Trans-(RS)-α-Methyl-N-(4-methanesulfonyloxymethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Methanesulfonyl chloride (0.34 mL, 4.44 mmol) was added to a solution ofcis RS) andtrans-(RS)-α-methyl-N-(4-hydroxymethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Example 271, 0.7 g, 1.48 mmol) andpyridine (0.6 mL, 7.4 mmol) in dichloromethane (20 mL) and the mixturewas stirred at room temperature for 24 hours. The solvent was evaporatedunder reduced pressure and the residue was dissolved in ethyl acetate.The mixture was washed with aqueous citric acid (10%), aqueous sodiumhydroxide (1M), dried (MgSO₄) and the solvent was evaporated underreduced pressure. The residue was purified by flash columnchromatography on silica gel, eluting with isohexane:EtOAc (70:30), togive the title compound as a colorless foam (335 mg, 41%). ¹H NMR (400MHz, CD₃OD) δ 7.81 (3H, s), 7.37–7.34 (2H, m), 7.25–7.21 (2H, m),7.17–7.15 (1H, m), 4.08 (2H, d, J 7.0 Hz), 3.87 (1H, q, J 7.1 Hz), 3.02(3H, s), 2.61–2.54 (1H, m), 2.40–2.32 (1H, m), 2.07–1.89 (3H, m),1.82–1.77 (1H, m), 1.71–1.62 (1H, m), 1.40–1.32 (1H, m), 1.37 (3H, d, J7.1 Hz), and 1.29–1.22 (1H, m).

EXAMPLE 273 (1R*,2′R*)- and (1R*,2′S*)-Ethyl[1-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-1-phenylcyclohex-4-ylidine]acetate

Ethyl (diethoxyphosphinyl)acetate (158 mL, 8.03 mmol) was added dropwiseto a slurry of sodium hydride (60% dispersion in mineral oil, 320 mg,8.00 mmol) in tetrahydrofuran (20 mL) and the mixture was stirred atroom temperature for 1 hours.(RS)-α-Methyl-N-(4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 3, 2.00 g, 4.37 mmol) in tetrahydrofuran (20 mL) was addeddropwise over 10 minutes and the mixture was stirred at room temperaturefor 3 hours. Water (150 mL) was added and the mixture was extracted withethyl acetate (3×150 mL). The combined organic fractions were washedwith brine (100 mL), dried (Na₂SO₄) and the solvent was evaporated underreduced pressure. The residue was triturated with isohexane (×2) and thesolid was collected and dried in vacuo to give the title compound (1.39g, 60%) as a mixture of diastereoisomers. The filtrate was evaporatedunder reduced pressure and the residue was purified by chromatography ona short column of silica gel, eluting with CH₂Cl₂ to give additionaltitle compound (0.61 g, 26%) as a mixture of diastereoisomers. ¹H NMR(400 MHz, CDCl₃) δ 7.79 (1H, s), 7.75 and 7.73 (Total 2H, each s),7.30–7.20 (5H, m), 5.69–5.61 (2H, m), 4.14 (2H, q, J 7 Hz), 3.68 (1H, q,J 7 Hz), 3.6–3.5 (1H, m), 2.8–1.9 (7H, m), 1.50 (3H, d, J 7 Hz), and1.25 (3H, t, J 7 Hz).

EXAMPLE 274 Trans-(RS)-Ethyl[1-({1-Oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-1-phenylcyclohex-4-yl]acetate

Sodium borohydride (288 mg, 7.58 mmol) was added to a mixture of(1R*,2′R*)- and (1R*,2′S*)-ethyl[1-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-1-phenylcyclohex-4-ylidine]acetate(Mixture of diastereoisomers, Example 273, 2.00 g, 3.80 mmol) and nickel(II) chloride hexahydrate (902 mg, 3.80 mmol) in ethanol (40 mL). Themixture was stirred at room temperature for 4 hours, then further nickel(II) chloride hexahydrate (450 mg, 1.90 mmol) and sodium borohydride(150 mg, 3.95 mmol) were added. The mixture was stirred at roomtemperature for 20 hours, then further nickel (II) chloride hexahydrate(450 mg, 1.90 mmol) and sodium borohydride (150 mg, 3.95 mmol) wereadded. The mixture was stirred at room temperature for 3 hours, thenwater (100 mL) was added and the ethanol was evaporated under reducedpressure. The residue was filtered through Hyflo™, washing with water(100 mL) and ethyl acetate (200 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic fractions were dried (Na₂SO₄), the solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography and MPLC on silica gel, eluting with isohexane/EtOAc(75:25), to give the title compound (975 mg, 49%). ¹H NMR (400 MHz,CDCl₃) δ 7.75 (1H, s), 7.64 (2H, s), 7.38–7.20 (5H, m), 5.49 (1H, br s),4.10 (2H, q, J 7 Hz), 3.51 (1, q, J 7 Hz), 2.58 (1H, br d, J 14 Hz),2.46 (1H, br d, J 14 Hz), 2.2–1.9 (5H, m), 1.75–1.6 (2H, m), 1.42 (3H,d, J 7 Hz), 1.22 (3H, t, J 7 Hz), and 1.25–1.05 (2H, m).

EXAMPLE 275Trans-(RS)-α-Methyl-N-(4-hydroxyethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Lithium borohydride (500 mg, 22.7 mmol) was added to a solution oftrans-(RS)-ethyl[1-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-1-phenylcyclohex-4-yl]acetate(Example 274, 975 mg, 1.84 mmol) in tetrahydrofuran/toluene (50:50, 40mL) and the mixture stirred at 60° C. for 6 hours. Additional lithiumborohydride (200 mg, 9.10 mmol) was added and the mixture was stirred at60° C. for 3 hours. The mixture was cooled to 0° C. and hydrochloricacid (2M, 30 mL) was added slowly. The mixture was poured into aqueoussodium carbonate (10%, 100 mL) and extracted with ethyl acetate (3×100mL). The combined organic fractions were dried (MgSO₄) and the solventwas evaporated under reduced pressure to give the title compound (927mg, 100%). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (1H, s), 7.65 (2H, s),7.38–7.15 (5H, m), 5.48 (1H, br s), 3.64 (2H, t, J 6.5 Hz), 3.51 (1H, q,J 7 Hz), 2.55 (1H, br d, J 14 Hz), 2.44 (1H, br d, J 14 Hz), 2.08 (2H,dq, J 11, 3 Hz), 1.75–1.40 (5H, m), 1.42 (3H, d, J 7 Hz), and 1.2–1.0(2H, m).

EXAMPLE 276Trans-(RS)-α-Methyl-N-(4-methanesulfonyloxyethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide

Methanesulfonyl chloride (440 μL, 5.68 mmol) was added dropwise to astirred, cooled (0° C.) solution oftrans-(RS)-α-methyl-N-(4-hydroxyethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 275, 920 mg, 1.89 mmol) and pyridine (760 μL, 9.4 mmol) indichloromethane (20 mL) and the mixture was stirred at room temperaturefor 20 hours. Further pyridine (380 μL, 4.7 mmol) and methanesulfonylchloride (220 μL, 2.84 mmol) were added and the mixture was stirred atroom temperature for 20 hours. Dichloromethane (200 mL) was added andthe mixture was washed with aqueous citric acid (10%, 100 mL), aqueoussodium hydroxide (1M, 100 mL), water (100 mL) and brine (100 mL), dried(Na₂SO₄) and the solvent was evaporated under reduced pressure to givethe title compound (1.025 g, 96%). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (1H,s), 7.64 (2H, s), 7.38–7.2 (5H, m), 5.48 (1H, br s), 4.20 (2H, t, J 6.5Hz), 3.48 (1H, q, J 7 Hz), 2.97 (3H, s), 2.58 (1H, br d, J 14 Hz), 2.48(1H, br d, J 14 Hz), 2.20–2.05 (2H, m), 1.75–1.50 (5H, m), 1.42 (3H, d,J 7 Hz), and 1.20–1.00 (2H, m).

EXAMPLE 277Trans-(RS)-α-Methyl-N-[4-(4-morpholinyl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Morpholine (31 μL, 0.36 mmol) was added to a solution oftrans-(RS)-α-methyl-N-(4-methanesulfonyloxymethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 272, 50 mg, 0.09 mmol) in acetonitrile (2 mL) and the mixturewas stirred at 80° C. for 3 days. The mixture was cooled the solvent wasevaporated under reduced pressure. Aqueous sodium hydroxide (1M) anddichloromethane were added. The layers were separated, the organicfraction was dried (MgSO₄) and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with CH₂Cl₂/MeOH (95:5 increasing to 90:10), to givethe title compound as a colorless solid (35 mg, 71%). m/z (ES⁺) 543(M+1).The following compounds were prepared fromtrans-(RS)-α-methyl-N-(4-methanesulfonyloxymethyl-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 272) ortrans-(RS)-α-methyl-N-(4-methanesulfonyloxyethyl-1-phenylcyclohexyl)-3,5-(trifluoromethyl)benzeneacetamide(Example 276) according to the method of Example 277, substituting asuitable amine for morpholine.

m/z (ES⁺) Ex. A B n —NR₂ Stereochemistry Formula M.W. (M + 1). 278 Me H1

Trans-(RS)- C₃₀H₃₆F₆N₂O₂ 570 571 279 Me H 1

Trans-(RS)- C₃₁H₃₈F₆N₂O₂ 584 585 280 Me H 1

Trans-(RS)- C₃₂H₃₈F₆N₂O₂ 596 597 281 Me H 1

-Trans-(3R,2′R)-Trans-(3R,2′S) C₃₃H₄₀F₆N₂O₃ 626 627 282 Me H 1

Trans-(RS)- C₃₄H₃₅F₆N₃O₂ 631 632 283 Me H 2

Trans-(RS)- C₃₀H₃₆F₆N₂O 554 555 284 Me H 2

Trans-(RS)- C₂₉H₃₄F₆N₂O₂ 556 557 285 Me H 2

Trans-(RS)- C30 H36 F6 N2 O2 570 571 286 Me H 2

Trans-(RS)- C₃₁H₃₈F₆N₂O₂ 584 585 287 Me H 2

Trans-(RS)- C₃₂H₄₀F₆N₂O₂ 598 599 288 Me H 2

Trans-(3R,2′R)-Trans-(3R,2′S)- C₃₄H₄₃F₆N₂O₃ 641 642 289 Me H 2

Trans-(RS)- C₃₃H₄₀F₆N₂O₂ 610 611 290 Me H 2

Trans-(RS)- C₃₅H₄₄F₆N₂O₂ 638 639 291 Me H 2

Trans-(RS)- C₃₅H₃₇F₆N₃O₂ 645 646

EXAMPLE 292 Trans-(3R,2′R)- andTrans-(3R,2′S)-3-Methyl-1-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcycloxyl]ethyl-3-piperidinecarboxylicacid

Prepared from trans-(3R,2′R)- and trans-(3R,2′S)-ethyl3-methyl-1-[4-({1-oxo-2-[3,5-bis(trifluoromethyl)phenyl]propyl}amino)-4-phenylcyclohexyl]ethyl-3-piperidinecarboxylate(Mixture of diastereoisomers, Example 288) according to the method ofExample 171. m/z (ES⁺) 614 (M+1).

EXAMPLE 293Cis-(RS)-α-Methyl-N-(6-phenyl-1-oxaspiro[2.5]oct-6-yl)-3,5-bis(trifluoromethyl)benzeneacetamide

3-Chlorobenzenecarboperoxoic acid (50–55%, 150 mg, 0.44 mmol) was addedto a solution of(RS)-α-methyl-N-(4-methylene-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 270, 135 mg, 0.297 mmol) in chloroform (5 mL) and the mixturewas stirred at room temperature for 2 hours. Saturated aqueous sodiumbisufite (10 mL) and aqueous sodium hydrogen carbonate (5%, 10 mL) wereadded and the mixture was stirred at room temperature for 1 hour. Thelayers were separated and the aqueous layer was extracted withdichloromethane (3×20 mL). The combined organic fractions were dried(Na₂SO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (75:25 increasing to 50:50), to give thetitle compound (30 mg, 21%). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (1H, s),7.71 (2H, s), 7.3–7.18 (5H, m), 5.61 (1H, br s), 3.68 (1H, q, J 7 Hz),2.66–2.53 (3H, m), 2.42–2.30 (1H, m), 2.25 (1H, ddd, J 14, 11, 4 Hz),2.13 (1H, ddd, J 14, 11, 4 Hz), 1.9–1.7 (2H, m), 1.6–1.4 (2H, m), and1.50 (3H, d, J 7 Hz).

EXAMPLE 294Cis-(RS)-α-Methyl-N-[4-hydroxy-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

A mixture of cis(RS)-α-methyl-N-(6-phenyl-1-oxaspiro[2.5]oct-6-yl)-3,5-bis(trifluoromethyl)benzeneacetamide(Example 293, 24 mg, 0.051 mmol) and 1-oxa-8-azaspiro[4.5]decane(Description 75, 70 mg) was stirred in the absence of solvent at 90° C.for 18 hours. The mixture was cooled and purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(95:5:0.5), to give the title compound (27 mg, 87%). ¹H NMR (400 MHz,CDCl₃) δ 7.76 (1H, s), 7.64 (2H, s), 7.35–7.20 (5H, m), 5.61 (1H, br s),3.80 (2H, t, J 7 Hz), 3.56 (1H, q, J 7 Hz), 2.75–2.62 (2H, m), 2.58–2.45(2H, m), 2.36 (1H, t, J 6 Hz), 2.30 (2H, s), 2.17 (2H, t, J 6 Hz), 1.89(2H, quin, J 7 Hz), 1.75–1.5 (7H, m), 1.42 (3H, d, J 7 Hz), and1.50–1.30 (2H, m). m/z (ES⁺) 613 (M+1).

EXAMPLE 295 (2R*,1′R*)- and(2S*,1′R*)-α-Methyl-N-[1-phenyl-4-(pyrid-3-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Tetrakistriphenylphosphine palladium(0) (196 mg, 0.17 mmol) was added toa degassed mixture of (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-(1-phenyl-4-{[(trifluoromethyl)sulfonyl]-oxy}cyclohex-3-enyl)-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Description 203, 0.5 g, 8.45 mmol),3-(tributylstannyl)pyridine (469 mg, 1.27 mmol) and lithium chloride(180 mg, 4.23 mmol) in toluene (25 mL) and the mixture was degassed andheated under reflux for 24 hours. The mixture was cooled, filtered andthe solvent was evaporated under reduced pressure. The residue waspurified by flash column chromatography on silica gel, eluting withisohexane/EtOAc (50:50) to give the title compound as a colorless solid(100 mg, 23%) as a 1:1 mixture of diastereoisomers. m/z (ES⁺) 519 (M+1).

EXAMPLE 296 (2R*,1′R*) and(2S*,1′R*)-α-Methyl-N-[1-phenyl-4-(pyrid-2-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-(1-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-enyl)-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Description 203) and2-(tributylstannyl)pyridine, according to the method of Example 295. m/z(ES⁺) 519 (M+1).

EXAMPLE 297 (2R*,1′R*) and(2S*,1′R*)-α-Methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Tetrakistriphenylphosphine palladium(0) (75 mg, 0.07 mmol) was added toa degassed suspension of (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N(1-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-enyl)-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Description 203, 418 mg, 0.71 mmol),4-pyridinylboronic acid (96 mg, 0.78 mmol), potassium triphosphate (451mg, 2.13 mmol) and ethylene glycol (45 L, 0.85 mmol) indimethylformamide (10 mL), and the mixture was stirred at 100° C. for 2hours. The mixture was cooled, poured into water (50 mL) and extractedwith diethyl ether (2×50 mL). The combined organic fractions were dried(MgSO₄) and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel,eluting with isohexane/EtOAc (50:50) to give the title compound as amixture of diastereoisomers (350 mg, 74%). m/z (ES⁺) 519 (M+1).

EXAMPLE 298 (2R*,1′R*)- and(2S*,1′R*)-α-Methyl-N-[1-phenyl-4-(2-methyl-pyrid-5-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-(1-phenyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-enyl)-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Description 203) and2-methyl-5-(trimethylstannyl)pyridine (J. Med. Chem. 1996, 39, 1846–56),according to the method of Example 295. m/z (ES⁺) 533 (M+1).

EXAMPLE 299Trans-(RS)-α-Methyl-N-[1-phenyl-4-pyrid-3-yl)cyclohex]-3,5-bis(trifluoromethyl)benzeneacetamide

Palladium on carbon (5%, 20 mg) was added to a solution of (2R*,1′R*)-and(2S*,1′R*)-α-methyl-N-[1-phenyl-4-(pyrid-3-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 295, 60 mg, 0.11 mmol) in ethyl acetate (20 mL) and the mixturewas stirred under an atmosphere of hydrogen (1 Atm.) for 4 hours. Themixture was filtered and the solvent was evaporated under reducedpressure. The residue was purified by flash column chromatography onsilica gel, eluting with isohexane:EtOAc (50:50 increasing to 25:75), togive the title compound as a colorless solid (12 mg, 21%). m/z (ES⁺) 521(M+1).

EXAMPLE 300Trans-(RS)-α-Methyl-N-[1-phenyl-4-(pyrid-2-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-[1-phenyl-4-(pyrid-2-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Example 296), according to the method ofExample 299. m/z (ES⁺) 521 (M+1).

EXAMPLE 301Cis-(RS)-α-Methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideandTrans-(RS)-α-Methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

A slurry of palladium on carbon (10%, 20 mg) in methanol (10 mL) wasadded to a solution of (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-(1-phenyl-4-(pyrid-4-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Description 297, 580 mg, 1.12 mmol) inethanol (20 mL) and the mixture was stirred under hydrogen (1 atm.) for2 hours. The mixture was filtered through Celite™ and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with isohexane/EtOAc(55:45) to givecis-(RS)-α-methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(120 mg, 21%); ¹H NMR (360 MHz, CD₃OD) δ 1.33–1.42 (1H, m), 1.47 (3H, d,J 7.2 Hz), 1.64–1.73 (2H, m), 1.81–2.01 (3H, m), 2.47 (1H, dd, J 13.7,2.5 Hz), 2.63–2.71 (2H, m), 4.08 (1H, q, J 7.2 Hz), 7.05 (2H, dd, J 5.0,1.4 Hz), 7.14–7.19 (1H, m), 7.22–7.27 (2H, m), 7.32–7.35 (2H, m), 7.91(1H, s), 8.18 (1H, s), and 8.37 (2H, dd, J 5.0, 1.4 Hz); m/z (ES⁺) 521(M+1); andtrans-(RS)-α-methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(50 mg, 9%); ¹H NMR (360 MHz, CD₃OD) δ 1.39 (3H, d, J 7.2 Hz), 1.49–1.71(2H, m), 1.80–1.92 (2H, m), 2.02–2.11 (2H, m), 2.68–2.83 (2H, m),2.91–2.95 (1H, m), 3.92 (1H, q, J 7.2 Hz), 7.16 (2H, d, J 5.8 Hz),7.20–7.28 (1H, m), 7.51–7.61 (2H, m), 7.62–7.67 (2H, m), 7.78 (2H, s),7.80 (1H, s), and 8.37 (2H, d, J 5.8 Hz). m/z (ES⁺) 521 (M+1).

EXAMPLE 302Trans-(RS)-α-Methyl-N-[1-phenyl-4-(2-methylpyrid-5-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from (2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-[1-phenyl-4-(2-methyl-pyrid-5-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers, Example 298), according to the method ofExample 299. m/z (ES⁺) 535 (M+1).

EXAMPLE 303Cis-(RS)-α-Methyl-N-[1-phenyl-4-(piperidin-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide,Trans-(RS)-α-Methyl-N-[1-phenyl-4-(piperidin-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide,Cis-(RS)-α-Methyl-N-{1-phenyl-4-[1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide,andTrans-(RS)-α-Methyl-N-{1-phenyl-4-[1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Benzyl bromide (127 μL, 1.06 mmol) was added to a solution of(2R*,1′R*)- and(2S*,1′R*)-α-methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohex-3-enyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Description 297, 275 mg, 0.53 mmol) inacetone (15 mL) and the mixture was heated under reflux for 16 hours.The mixture was cooled and the solvent was evaporated under reducedpressure. The residue was dissolved in methanol (17 mL) and water (3mL), sodium borohydride (80 mg, 2.12 mmol) was added, and the mixturewas heated under reflux for 3 hours. The mixture was cooled and thesolvent was evaporated under reduced pressure. Ethyl acetate (40 mL) andaqueous sodium hydrogen carbonate (10%, 40 mL) were added and the layerswere separated. The organic fraction was dried (MgSO₄) and the solventwas evaporated under reduced pressure. The residue was dissolved inethyl acetate (8 mL) and a slurry of palladium on carbon (10%, 20 mg) inethyl acetate (10 mL) was added. The mixture was shaken under hydrogen(50 psi) for 16 hours. A slurry of palladium on carbon (10%, 20 mg) inethanol (10 mL) and hydrochloric acid (2M, 2 mL) was added and themixture was shaken under hydrogen (50 psi) for 72 hours. The mixture wasfiltered through Celite™, washing with ethanol, and the solvent wasevaporated under reduced pressure. Ethyl acetate (10 mL) and aqueoussodium hydrogen carbonate (10%, 10 mL) were added and the layers wereseparated. The organic fraction was dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by MPLCchromatography on silica gel, eluting with CH₂Cl₂/MeOH/Et₃N (90:10:1),to givecis-(RS)-α-methyl-N-[1-phenyl-4-(piperidin-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(60 mg, 21%); ¹H NMR (360 MHz, CD₃OD) δ 0.84–4.90 (1H, m), 1.16–1.45(6H, m), 1.43 (3H, d, J 7.2 Hz), 1.54–1.69 (5H, m), 2.32–2.37 (1H, m),2.57–270 (3H, m), 3.17–3.22 (2H, m), 4.02 (1H, q, J 7.2H), 7.12–7.30(5H, m), 7.88 (2H, s), and 7.95 (1H, s); m/z (ES⁺) 527 (M+1);trans-(RS)-α-methyl-N-[1-phenyl-4-(piperidin-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(26 mg, 9%); ¹H NMR (400 MHz, CD₃OD) δ 0.98–1.45 (9H, m), 1.60–1.72 (1H,m), 1.88–1.91 (1H, m), 1.93–1.96 (4H, m), 2.47–2.53 (1H, m), 2.66–2.71(1H, m), 2.84–2.91 (2H, m), 3.46–3.49 (2H, m), 3.82 (1H, q, J 7.2 Hz),7.13–7.39 (5H, m), 7.78 (2H, s), and 7.80 (1H, s); m/z (ES⁺) 527 (M+1);and a mixture of 2 isomeric compounds (20 mg) which were furtherpurified by preparative thin layer chromatography on silica gel, elutingwith CH₂Cl₂/MeOH/Et₃N (90:10:1), to givecis-(RS)-α-methyl-N-[1-phenyl-4-[1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(5 mg, 2%); ¹H NMR (360 MHz, CDCl₃) δ 0.74–0.98 (2H, m), 1.04–1.39 (4H,m), 1.38 (3H, d, J 7.2 Hz), 1.39–1.73 (6H, m), 1.83–1.90 (2H, m),2.32–2.46 (2H, m), 2.88–2.91 (2H, m), 3.49 (2H, s), 3.68 (1H, q, J 7.2Hz), 7.13–7.32 (10H, m), and 7.77 (3H, s); m/z (ES⁺) 617 (M+1); andtrans-(RS)-α-methyl-N-{1-phenyl-4-[1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(3 mg, 1%); ¹H NMR (360 MHz, CDCl₃) δ 0.94–1.25 (4H, m), 1.38 (3H, d, J7.2 Hz), 1.50–1.68 (6H, m), 1.76–1.86 (2H, m), 1.97–2.05 (2H, m),2.43–2.58 (2H, m), 2.83–2.87 (2H, m), 3.44–3.49 (3H, m), 7.20–7.37 (10H,m), 7.63 (2H, s), and 7.74 (1H, s). m/z (ES⁺) 617 (M+1).

EXAMPLE 304Trans-(RS)-α-Methyl-N-[1-phenyl-4-{1-(1-methylethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

A mixture of sodium cyanoborohydride (2.4 mg, 0.038 mmol) and zincchloride (2.6 mg, 0.019 mmol) in methanol (2 mL) was sonicated until thesolid dissolved, then added to a solution oftrans-(RS)-α-methyl-N-[1-phenyl-4-(piperidin-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 303, 10 mg, 0.019 mmol) and acetone (7 μL, 0.019 mmol) inmethanol (2 mL). The mixture was stirred at room temperature overnight,then the solvent was evaporated under reduced pressure and saturatedaqueous sodium hydrogen carbonate (3 mL) and dichloromethane (3 mL) wereadded. The layers were separated and the organic fraction was pouredonto an SCX cartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridgewas washed with methanol (4×2 mL), then eluted with methanolic ammonia(2M, 2×2 mL). The solvent was evaporated under reduced pressure to givethe title compound as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 1.03(3H, d, J 7.2 Hz), 1.03–1.27 (4H, m), 1.33 (6H, d, J 7.0 Hz), 1.56–1.73(5H, m), 1.85–1.96 (2H, m), 2.01–2.15 (2H, m), 2.41–2.49 (1H, m),2.61–2.66 (2H, m), 2.86–2.90 (2H, m), 3.16–3.25 (1H, m), 3.82 (1H, q, J7.2 Hz), 7.11–7.36 (5S, m), 7.78 (2H, s), and 7.79 (1H, s). m/z (ES⁺)569 (M+1).

EXAMPLE 305Trans-(RS)-α-Methyl-N-{1-phenyl-4-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared fromtrans-(RS)-α-methyl-N-[1-phenyl-4-(piperidin-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 303) according to the method of Example 304, substitutingpyran-4-one for acetone. m/z (ES⁺) 611 (M+1).

EXAMPLE 306Trans-(RS)-α-Methyl-N-{1-phenyl-4-[1,2,3,6-tetrahydro-1-(phenylmethyl)pyrid-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Benzyl bromide (87 μL, 0.73 mmol) was added to a solution oftrans-(RS)-α-methyl-N-[1-phenyl-4-(pyrid-4-yl)cyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 301, 190 mg, 0.36 mmol) in acetone (3 mL) and the mixture washeated under reflux for 16 hours. The mixture was cooled and the solventwas evaporated under reduced pressure. The residue was dissolved inmethanol/water (6:1, 14 mL) and sodium borohydride (54 mg 1.5 mmol) wasadded. The mixture was heated under reflux for 3 hours, cooled, and thesolvent was evaporated under reduced pressure. Dichloromethane (10 mL)and aqueous sodium hydrogen carbonate (10%, 5 mL) were added and thelayers were separated. The organic fraction was poured onto an SCXcartridge (Varian Bond Elut™; 10 mL/500 mg). The cartridge was washedwith methanol (4×2 mL), then eluted with methanolic ammonia (2M, 2×2mL). The solvent was evaporated under reduced pressure and the residuewas purified by preparative thin layer chromatography on silica gel togive the title compound (60 mg, 30%). m/z (ES⁺) 614 (M+1).

EXAMPLE 307 (2R*,3′R*,4′R*)-Trans- and(2S*,3′R*,4′R*)-Trans-α-Methyl-N-{1-phenyl-4-[3-hydroxy-1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamideand (2R*,3′R*,4′R*)-Cis- and(2S*,3′R*,4′R*)-Cis-α-Methyl-N-{1-phenyl-4-[3-hydroxy-1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide

Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 0.332 mL) wasadded to a solution oftrans-(RS)-α-methyl-N-{1-phenyl-4-[1,2,3,6-tetrahydro-1-phenylmethyl)pyrid-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(Example 306, 102 mg, 0.166 mmol) in tetrahydrofuran (5 mL) and themixture was stirred at room temperature for 72 hours. A mixture ofaqueous sodium hydroxide (4M, 2.5 mL) and aqueous hydrogen peroxide(37%, 2.5 mL) was added and the mixture was stirred at room temperaturefor 2 hours. The mixture was extracted with ethyl acetate (2×25 mL), thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer chromatography on silica gel to give(2R*,3′R*,4′R*)-trans- and(2S*,3′R*,4′R*)-trans-(RS)-α-methyl-N-{1-phenyl-4-[3-hydroxy-1-(phenylmethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers); ¹H NMR (400 MHz, CD₃OD) δ 1.20–1.33 (6H,m), 1.42 (3H, d, J 7.2 Hz), 1.52–1.91 (6H, m), 2.23–2.79 (3H, m),2.92–3.02 (1H, m), 3.38–3.53 (3H, m), 4.07 (1H, q, J 7.2 Hz), 7.12–7.42(10H, m), and 7.72–7.79 (3H, m); m/z (ES⁺) 633 (M+1); and(2R*,3′R*,4′R*)-cis- and(2S*,3′R*,4′R*)-cis-(RS)-α-methyl-N-[1-phenyl-4-{3-hydroxy-1-(phenylethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide(mixture of diastereoisomers); ¹H NMR (400 MHz, CD₃OD) δ 0.82–4.96 (2H,m), 1.00–1.13 (1H, m), 1.19–1.49 (4H, m), 1.42 (3H, d, J 7.2 Hz),1.62–1.90 (5H, m), 2.25–2.39 (1H, m), 2.50–2.69 (1H, m), 2.71–2.81 (1H,m), 2.97–3.01 (1H, m), 4.01 (1H, q, J 7.2 Hz), 7.11–7.75 (10H, m), and7.79–8.01 (3H, m); m/z (ES⁺) 633 (M+1).

EXAMPLE 308 (1R*,3S*,4R*)- and(1R*,3R*,4R*)-α,α-Dimethyl-N-[3-hydroxy-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Prepared from cis-(RS)- andtrans-(RS)-α,α-dimethyl-N-(3-hydroxy-4-oxo-1-phenylcyclohexyl)-3,5-bis(trifluoromethyl)benzeneacetamide(Mixture of diastereoisomers, Example 59) and1-oxa-8-azaspiro[4.5]decane (Description 75) according to the method ofExample 33. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (1H, s), 7.63 (2H, s),7.40–7.20 (5H, m), 5.35 (1H, br s), 3.77 (2H, br t, J 7 Hz), 3.40–3.30(1H, m), 2.90–2.65 (3H, m), 2.50–2.20 (4H, m), 2.10–1.55 (11H, m), 1.48(3H, s), 1.47 (3H, s), and 1.25 (br q, J 13 Hz). m/z (ES⁺) 613 (M+1).

EXAMPLE 309(1R*,3S*,4R*)-α,α-Dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideand(1S*,3S*,4R*)-α,α-Dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide

Sodium triacetoxyborohydride (307 mg, 1.45 mmol) was added to a mixtureof(1R*,3S*)-α,α-dimethyl-N-[3-fluoro-4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide(Example 58, 490 mg, 0.97 mmol), 2-oxa-8-azaspiro[4.5]decanehydrochloride (Description 86, 204 mg, 1.37 mmol) and triethylamine(1.34 mL, 9.7 mmol) in 1,2-dichloroethane (15 mL) and the mixture wasstirred at room temperature for 3 days. Further sodiumtriacetoxyborohydride (103 mg, 0.49 mmol) was added and the mixture wasstirred at room temperature for 24 hours. The mixture was basified withaqueous sodium hydroxide (1M) and extracted with dichloromethane. Thecombined organic fractions were dried (MgSO₄) and the solvent wasevaporated under reduced pressure. The residue was purified by MPLC onsilica gel, eluting with CH₂Cl₂/MeOH (97.5:2.5), to give(1R*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideas a colorless foam (18 mg, 3%); ¹H NMR (400 MHz, CDCl₃) δ 7.81 (1H, s),7.70 (2H, s), 7.36–7.23 (5H, m), 5.13 (1H, s), 4.98 (1H, br d, J 48.5Hz), 3.81 (2H, t, J 7.2Hz), 2.89–2.68 (3H, m), 3.67–2.42 (4H, m),2.41–2.38 (2H, m), 1.89–1.86 (1H, m), 1.73–1.71 (1H, m), 1.68 (2H, t, J7.2 Hz), 1.63–1.58 (6H, m), and 1.53 (6H, d, 3.4 Hz). m/z (ES⁺) 615(M+1); and(1S*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamideas a colorless foam (280 mg, 47%). ¹H NMR (400 MHz, CDCl₃) δ 7.81 (2H,s), 7.79 (1H, s), 7.32–7.21 (1H, s), 6.41 (1H, d, J 10.5 Hz), 5.06 (1H,br d, J 50.0 Hz), 3.87–3.83 (2H, m), 3.00–2.96 (1H, m), 2.60–2.39 (4H,m), 2.30–2.22 (2H, m), 2.01–1.93 (1H, m), 1.77–1.70 (3H, m), 1.65–1.50(8H, m), and 1.60 (6H, d, J 6.9 Hz). m/z (ES⁺) 615 (M+1).

EXAMPLE 310Trans-N-{4-[3-Oxa-4-phenylpiperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)-α-oxobenzeneacetamideHydrochloride

Triethylamine (84 μL, 61 mg, 0.6 mmol) was added to a stirred, cooled(0° C.) mixture oftrans-4-(3-oxo-4-phenyl-1-piperazinyl)-1-phenylcyclohexylamine(Description 193, 70 mg, 0.2 mmol),3,5-bis(trifluoromethyl)-α-oxobenzeneacetic acid (Description 48, 86 mg,0.3 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (76 mg, 0.3mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for5 minutes, then at room temperature for 22 hours. Saturated aqueoussodium hydrogen carbonate (20 mL) and water (10 mL) were added andmixture was extracted with dichloromethane (3×20 mL). The combinedorganic fractions were dried (MgSO₄), the solvent was evaporated underreduced pressure and the residue was purified by flash columnchromatography on silica gel, eluting with CH₂Cl₂/MeOH/NH₃(Aq.)(98:2:0.2). The residue was dissolved in tetrahydrofuran (3 mL), cooledin ice and ethereal hydrogen chloride (1M, 0.2 mL) was added. Themixture was refrigerated and the solid was collected and dried in vacuoto give the title compound as a colorless solid (45 mg, 34%), m.p.252–255° C. (Dec.). m/z (ES⁺) 618 (M+1).

EXAMPLE 311(RS)-Trans-N-{4-[3-Oxa-4-phenylpiperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)-α-hydroxybenzeneacetamideHydrochloride

Sodium borohydride (9 mg, 0.24 mmol) was added to a stirred, cooled (0°C.) suspension oftrans-N-{4-[3-oxa-4-phenylpiperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)-α-oxobenzeneacetamidehydrochloride (Example 310, 54 mg, 82 μmol) in ethanol-water (95:5, 5mL) and the mixture was stirred at 0° C. for 1 hour. The solvent wasevaporated under reduced pressure, saturated aqueous sodium hydrogencarbonate (20 mL) and water (10 mL) were added and mixture was extractedwith dichloromethane (3×20 mL). The combined organic fractions weredried (MgSO₄), the solvent was evaporated under reduced pressure and theresidue was purified by MPLC on silica gel, eluting withCH₂Cl₂/MeOH/NH₃(Aq.) (97:3:0.3 increasing to 96:4:0.4). The residue wasdissolved in ethanol (3 mL), cooled in ice and ethereal hydrogenchloride (1M, 0.15 mL) was added. The solvent was evaporated underreduced pressure and the residue was triturated with ether-ethanol(95:5, 3 mL). The solid was collected and dried in vacuo to give thetitle compound as a colorless solid (32 mg, 60%), m.p. 153–155° C. m/z(ES⁺) 620 (M+1).

1. A compound of the formula (I):

wherein ring A is a phenyl or pyridyl ring; X represents a linkerselected from the group consisting of:

R¹ represents fluoroC₁₋₆alkyl or halogen; R² represents hydrogen orhalogen; R³ represents hydrogen, halogen, or fluoroC₁₋₆alkyl; R⁴ ishydrogen, halogen or CF₃; R⁵ is hydrogen, halogen or CF₃; R⁶ representshydrogen, hydroxy or a C₁₋₄alkyl group optionally substituted by ahydroxy group; R⁷ represents —(CH₂)_(n)NR⁸R⁹, where R⁸ and R⁹, togetherwith the nitrogen atom to which they are attached, represent aheteroaliphatic ring selected from the group consisting of:

R¹⁰ and R¹¹ each independently represent hydrogen, halogen, hydroxy,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyC₁₋₆alkyl, fluoroC₁₋₆alkyl,C₁₋₆alkoxy, (CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (C₂₋₆alkenyl)aryl,(C₂₋₆alkynyl)aryl, (CH₂)_(q)heterocyclyl, (CH₂)_(q)NR^(a)R^(b),O(CH₂)_(q)C₃₋₇cycloalkyl, O(CH₂)_(q)aryl, O(CH₂)_(q)heterocyclyl,O(CH₂)_(p)NR^(a)R^(b), OC(O)C₁₋₆alkyl, C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, C(O)(CH₂)_(q)NR^(a)R^(b), CO₂H, CO₂C₁₋₆alkyl,CO₂(CH₂)_(q)C₃₋₇cycloalkyl, CO₂(CH₂)_(q)aryl, CO₂(CH₂)_(q)heterocyclylor CO₂(CH₂)_(p)NR^(a)R^(b), where R^(a) and R^(b) each independentlyrepresent hydrogen, C₁₋₄alkyl, C₃₋₅cycloalkyl, fluoroC₁₋₄alkyl orCH₂CO₂C₁₋₄alkyl; R¹² represents hydrogen, C₁₋₆alkyl,(CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl, CHO,C(O)C₁₋₆alkyl, C(O)(CH₂)_(q)C₃₋₇cycloalkyl, C(O)(CH₂)_(q)aryl,C(O)(CH₂)_(q)heterocyclyl, CO₂C₁₋₆alkyl, CO₂(CH₂)_(q)C₃₋₇cycloalkyl,CO₂(CH₂)_(q)aryl, CO₂(CH₂)_(q)heterocyclyl or CO₂(CH₂)_(p)NR^(a)R^(b);R¹³ represents hydrogen, C₁₋₆alkyl or C(O)C₁₋₆alkyl; R¹⁴ and R¹⁵ eachindependently represent hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkenyl,hydroxyC₁₋₆alkyl, C₁₋₄alkoxyC₁₋₄alkyl, (CH₂)_(p)NR^(a)R^(b), CHO,C(O)C₁₋₆alkyl or CO₂C₁₋₆alkyl; or, R¹⁴ and R¹⁵ together represent—CH₂CH₂—; R¹⁸ and R¹⁹ each independently represent hydrogen, halogen,hydroxy, C₁₋₆alkyl or oxo (═O); R²⁰ represents hydrogen, halogen,hydroxy, C₁₋₄alkyl, hydroxyC₁₋₄alkyl or fluoroC₁₋₄alkyl; R^(21a)represents hydrogen, halogen or hydroxy and R^(21b) represents hydrogen;or R^(21a) and R^(21b) both represent fluorine or together represent oxo(═O); n is zero, 1 or 2; m is 1 or 2; p is 1, 2, 3 or 4; q is zero, 1,2, 3 or 4; and s is 1, 2 or 3; or a pharmaceutically acceptable salt oran N-oxide thereof.
 2. The compound of claim 1 wherein R¹ is CF₃.
 3. Thecompound of claim 1 wherein R² is hydrogen.
 4. The compound of claim 1wherein R³ is CF₃.
 5. The compound of claim 1 wherein R⁴ is hydrogen. 6.The compound of claim 1 wherein R⁵ is halogen.
 7. The compound of claim6 wherein R⁵ is fluorine.
 8. The compound of claim 1 wherein R⁶ ishydrogen.
 9. The compound of claim 8 wherein R⁸ and R⁹ together with thenitrogen atom to which they are attached represent a heteroaliphaticring selected from the group consisting of:


10. The compound as claimed in claim 9 wherein R¹⁰ represents hydrogen,hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyC₁₋₆alkyl,fluoroC₁₋₆alkyl, (C₂₋₆alkynyl)aryl, (CH₂)_(q)aryl,(CH₂)_(q)heterocyclyl, (CH₂)_(q)NR^(a)R^(b), OC(O)C₁₋₆alkyl,C(O)(CH₂)_(q)NR^(a)R^(b), CO₂H or CO₂C₁₋₆alkyl; and R¹¹ representshydrogen, halogen, hydroxy, C₁₋₆alkyl or (CH₂)_(q)NR^(a)R^(b).
 11. Thecompound of claim 9 wherein R¹² represents hydrogen, C₁₋₆alkyl,(CH₂)_(q)C₃₋₇cycloalkyl, (CH₂)_(q)aryl, (CH₂)_(q)heterocyclyl, CHO,C(O)C₁₋₆alkyl, C(O)C₃₋₇cycloalkyl, C(O)(CH₂)_(q)aryl or CO₂C₁₋₆alkyl.12. The compound of claim 1 wherein the ring A is a phenyl ring.
 13. Thecompound of claim 1 wherein X is the linker:


14. The compound of claim 13 wherein X is the linker:


15. The compound of claim 1 of the formula (Ia):

wherein A¹ is fluorine or CF₃; A² is fluorine or CF₃; A³ is fluorine orhydrogen; or a pharmaceutically acceptable salt thereof.
 16. A compoundwhich selected from the group consisting of: cis-(RS)- andtrans-(RS)-α-methyl-N-{4-[4-hydroxymethyl-4-(methoxymethyl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethylbenzeneacetamide;trans-(RS)-α-methyl-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[4-(2-oxa-4-oxo-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[4-(1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(2R*,3′R*)- andtrans-(2R*,3′S*)-α-methyl-N-[4-(3-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(2R*,4′R*)- andtrans-(2R*,4′S*)-α-methyl-N-[4-(4-hydroxy-1-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[4-(1-oxa-3-oxa-9-azaspiro[5.5]undecan-9-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-{4-[4-(phenylmethyl)piperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[4-(4-methylpiperazin-1-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-{4-[4-(1-methylethyl)piperazin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-{4-[4-(1-methylethyl)-2-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[4-(2,2-dimethyl-4-phenylmethyl-1-piperazinyl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-{4-[4-(1,1-dimethylethyl)-2-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(S)-α-methyl-N-{4-[4-(4-fluorophenyl)-3-oxo-1-piperazinyl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-{4-[2-oxo-4-(piperidin-1-yl)piperidin-1-yl]-1-phenylcyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[4-(4-oxopiperidin-1-yl)methyl]-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide;trans-(RS)-α-methyl-N-[4-(4-hydroxypiperidin-1-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethylbenzeneacetamide;cis-(RS)-α-methyl-N-[4-hydroxy-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)methyl-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;trans-(RS)-α-methyl-N-[1-phenyl-4-{1-(1-methylethyl)piperidin-4-yl]cyclohexyl}-3,5-bis(trifluoromethyl)benzeneacetamide;(1R*,3S*,4R*)- and(1R*,3R*,4R*)-α,α-dimethyl-N-[3-hydroxy-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;(1R*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide;or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 wherein the stereochemistry of the 1- and 4-positions is as shown informula (Ib):


18. A pharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 19. A method for the treatment of pain,inflammation, migraine, emesis, postherpetic neuralgia, depression oranxiety, which method comprises administration to a patient in needthereof of a tachykinin reducing amount of the compound of claim 1 or apharmaceutically acceptable salt thereof.